Therapeutic metal-drug coordination complexes

Abstract

The present disclosure relates in some aspects to therapeutic metal complexes comprising a pharmacologically active agent coordinated to a metal. In some aspects, the disclosure further relates to methods of synthesizing the complexes, compositions containing the complexes, and methods of using the complexes, including their administration to subjects. In some aspects, useful features of the complexes include controlling active agent release pharmacokinetics, reducing side effects, and improving safety profiles.

Description

[0001] 2025-12-15 THERAPEUTIC METAL-DRUG COORDINATION COMPLEXES

[0002] Matthew G. Cowan, Gregory E. Dwulet

[0003] CROSS-REFERENCE

[0004]

[0001] Priority is claimed under PCT Article 8(1) and Rule 4.10 to U. S. Provisional App. No.

[0005] 63 / 733,728, filed December 13, 2024, and incorporated by reference for all purposes as if fully set forth herein. This application is timely filed on the first working day following Saturday, December 13, 2025, pursuant to PCT Rule 80.5 and MPEP §710.05.

[0006] FIELD OF THE INVENTION

[0007]

[0002] The present disclosure relates in some aspects to therapeutic metal complexes comprising a pharmacologically active agent coordinated to a metal. In some aspects, the disclosure further relates to methods of synthesizing the complexes, compositions containing the complexes, and methods of using the complexes, including their administration to subjects. In some aspects, useful features of the complexes include controlling active agent release pharmacokinetics, reducing side effects, and improving safety profiles.

[0008] BACKGROUND

[0009]

[0003] Psychedelic and empathogenic (or entactogenic) drugs have received substantial attention for their potential therapeutic utility in a variety of clinical contexts, including the treatment of psychiatric and neurological conditions. One representative example is 3,4-methylenedioxymethamphetamine (MDMA), commonly known as ecstasy, which has been studied extensively for its potential benefits in the treatment of conditions such as post-traumatic stress disorder (PTSD). Clinical investigations have demonstrated that MDMA can facilitate profound psychotherapeutic experiences, offering patients significant relief where traditional treatments have failed. Despite these promising results, clinical use of MDMA has been limited by concerns regarding safety, tolerability, pharmacokinetics, and off-target effects. Such concerns include neurotoxicity, oxidative stress, undesirable metabolic pathways, inter-individual variability in exposure, and the risk of adverse psychological or physiological reactions. More generally, many drugs that target brain neurotransmitter systems exhibit limitations in bioavailability, tissue distribution, metabolic fate, and overall safety. There is therefore a need for new approaches that can minimize side effects, improve efficacy, and enable greater patient access.

[0010] INCORPORATION BY REFERENCE

[0011]

[0004] Each cited patent, publication, and non-patent literature is incorporated by reference in its entirety, as if each was incorporated by reference individually, and as if each is fully set forth herein. However, no such citation should be construed as an admission that a cited reference comes from an area that is analogous or directly applicable to the invention, nor should any citation be construed as an 2025-12-15 admission that a document or underlying information, in any jurisdiction, is prior art or is part of the common general knowledge in the art.

[0012] BRIEF SUMMARY OF THE INVENTION

[0013]

[0005] The following is a simplified summary of some embodiments of the invention in order to provide a basic understanding thereof. This summary is not an extensive overview of the invention. It is not intended to identify key or critical elements of the invention or to delineate the scope thereof. Its purpose is to present some embodiments and aspects of the invention in a simplified form as a prelude to the more detailed description that follows.

[0014]

[0006] In one aspect, provided is a metal-drug coordination complex comprising a metal coordinated to one or more pharmacologically active agents having the structure of Formula (I),

[0015]

[0016] wherein L is a ligand moiety or H; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0017]

[0007] In embodiments, L is a ligand moiety. In embodiments, the ligand moiety comprises an amino acid. In embodiments, the amino acid is alanine, arginine, asparagine, aspartic acid, cysteine, selenocysteine, / V-acetylcysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine. In embodiments, the amino acid is an (L)-isomer. In embodiments, the amino acid is a (D)-isomer.

[0018]

[0008] In embodiments, the one or more pharmacologically active agents have the structure of:

[0019]

[0020] wherein R is an amino acid side chain, and R' is H or— COCH3.

[0021]

[0009] In embodiments, R' is H. In embodiments, R' is — COCH3.

[0022]

[0010] In embodiments, the complex has the structure of:

[0023]

[0024] 2025-12-15

[0011] In embodiments, the complex has the structure of:

[0025]

[0026]

[0012] In embodiments, R is C1-C12alkyl, C1-C6hydroxyalkyl, C1-C6alkylthio, C1-C6aminoalkyl, C1-C6carboxyalkyl, C1-C6alkylene–C6-C12aryl, C1-C6alkylene–(3- to 10-membered heteroaryl), C1-C6alkylene–guanidino, C1-C6alkylene–CONH2, or H; or R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl. In embodiments, R is C1-C6alkyl. In embodiments, R is isopropyl. In embodiments, R is methyl. In embodiments, R is sec-butyl. In embodiments, R is isobutyl. In embodiments, R is C1-C6hydroxyalkyl. In embodiments, R is -CH2OH. In embodiments, R is C1-C6thioalkyl. In embodiments, R is -CH2SH. In embodiments, R is -(CH2)2SCH3. In embodiments, R is C1-C6aminoalkyl. In embodiments, R is -(CH2)4NH2or -(CH2)4NH3+. In embodiments, R is C1-C6carboxyalkyl. In embodiments, R is -CH2COOH or -CH2COO’. In embodiments, R is -(CH2)2COOH or -(CH2)2C00‘. In embodiments, R is C1-C6alkylene-C6-C12aryl. In embodiments, R is -CH2-phenyl. In embodiments, R is -CH2-(4-hydroxyphenyl). In embodiments, R is C1-C6alkylene— (3- to 10-membered heteroaryl). In embodiments, R is –CH2–imidazol-4-yl. In embodiments, R is — CH2— (3-indolyl). In embodiments, R is C1-C6alkylene— guanidino. In embodiments, R is —(CH2)3— guanidino. In embodiments, R is C1-C6alkylene-CONH2. In embodiments, R is -CH2CONH2or-CH2CONH2. In embodiments, R is -(CH2)2CONH2or -(CH2)2CONH2. In embodiments, R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl. In embodiments, R and R' are taken together with the intervening atoms to form a pyrrolidinyl. In embodiments, R is H.

[0027]

[0013] In embodiments, R' is — COCH3.

[0028]

[0014] In embodiments, L is H.

[0029]

[0015] In embodiments, the complex comprises two or more pharmacologically active agents coordinated to the metal. In embodiments, the complex comprises three or more pharmacologically active agents coordinated to the metal.

[0030]

[0016] In embodiments, the metal is zinc (Zn), iron (Fe), silver (Ag), cobalt (Co), copper (Cu), nickel (Ni), manganese (Mn), gold (Au), palladium (Pd), scandium (Sc), molybdenum (Mo), tungsten (W), chromium (Cr), vanadium (V), titanium (Ti), gallium (Ga), germanium (Ge), arsenic (As), selenium (Se), yttrium (Y), zirconium (Zr), niobium (Nb), technetium (Tc), ruthenium (Ru), rhodium (Rh), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), hafnium (Hf), tantalum (Ta), rhenium (Re), osmium (Os), iridium (Ir), platinum (Pt), mercury (Hg), thallium (TI), lead (Pb), or bismuth (Bi). 2025-12-15

[0017] In embodiments, the metal is Zn, Fe, Ag, Co, Cu, Ni, Mn, Au, Pd, Sc, Mo, W, Cr, or V.

[0031]

[0018] In embodiments, the metal is Zn(ll), Fe(ll), Fe(lll), Mn(ll), Mn(lll), Mn(IV), Mn(V), Mn(VI), Ni(ll), Ni(lll), Ag(l), Co(ll), Co(lll), Cu(l), Cu(ll), Au(l), Au(lll), Pd(ll), Sc(lll), Mo(ll), Mo(lll), Mo(IV), Mo(V), Mo(VI), W(ll), W(lll), W(IV), W(V), W(VI), Cr(ll), Cr(lll), Cr(IV), Cr(V), Cr(VI), V(ll), V(lll), V(IV), or V(V). In embodiments, the metal is Zn(ll), Fe(ll), Fe(lll), Mn(ll), Mn(lll), Mn(IV), Ni(ll), Ni(lll), Co(ll), Cu(l), Cu(ll), Sc(lll), Mo(ll), Mo(lll), or Mo(IV).

[0032]

[0019] In embodiments, the metal is Zn(ll). In embodiments, the metal is Fe(ll) or Fe(lll). In embodiments, the metal is Fe(ll). In embodiments, the metal is Fe(lll). In embodiments, the metal is Mn(ll), Mn(lll), Mn(IV), Mn(V), or Mn(VI). In embodiments, the metal is Ni(ll) or Ni(lll). In embodiments, the metal is Ag(l). In embodiments, the metal is Co(ll) or Co(lll). In embodiments, the metal is Cu(l) or Cu(ll). In embodiments, the metal is Au(l) or Au(lll). In embodiments, the metal is Pd(ll). In embodiments, the metal is Sc(lll). In embodiments, the metal is Mo(ll), Mo(lll), Mo(IV), Mo(V), or Mo(VI). In embodiments, the metal is W(ll), W(lll), W(IV), W(V), or W(VI). In embodiments, the metal is Cr(ll), Cr(lll), Cr(IV), Cr(V), or Cr(VI). In embodiments, the metal is V(ll), V(lll), V(IV), or V(V).

[0033]

[0020] In embodiments, the metal is a metal ion. In embodiments, the metal ion is a Zn, Fe, Ag, Co, Cu, Ni, Mn, Au, Pd, Sc, Mo, W, Cr, or V ion.

[0034]

[0021] In embodiments, the complex is four-coordinate. In embodiments, the complex has square planar geometry. In embodiments, the complex has tetrahedral geometry.

[0035]

[0022] In embodiments, the complex is five-coordinate. In embodiments, the complex has square pyramidal or trigonal bipyramidal geometry.

[0036]

[0023] In embodiments, the complex is six-coordinate. In embodiments, the complex has octahedral geometry.

[0037]

[0024] In embodiments, the complex further comprises one or more solvent molecules and / or coordinating anions coordinated to the metal. In embodiments, the complex further comprises two or more solvent molecules and / or coordinating anions coordinated to the metal.

[0038]

[0025] In another aspect, provided is a metal-drug coordination complex selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0039]

[0026] In another aspect, provided is a metal-drug coordination complex selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0040]

[0027] In another aspect, provided is a metal-drug coordination complex selected from the group consisting of: 2025-12-15

[0041]

[0042] or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0043]

[0028] In embodiments, the complex comprises no ionic interactions between the metal and the pharmacologically active agent.

[0044]

[0029] In embodiments, the complex is in crystalline form. 2025-12-15

[0030] In another aspect, provided is a pharmaceutical composition comprising the complex of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.

[0045]

[0031] In embodiments, the pharmaceutical composition is in unit dosage form. In embodiments, the pharmaceutical composition is formulated for oral, mucosal, rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, or intranasal administration. In embodiments, the pharmaceutical composition comprises the complex in a total amount of between about 10 mg and about 300 mg.

[0046]

[0032] In embodiments, the pharmaceutical composition further comprises one or more additional active compounds. In embodiments, the one or more additional active compounds are selected from the group consisting of amino acids, amino acid derivatives, amino acid analogs, amino acid mimetics, antioxidants, anti-inflammatory agents, neuroprotective agents, analgesic, antinociceptive, antineuropathic agents, anxiolytic agents, antidepressant agents, anti-PTSD agents, empathogenic (entactogenic) agents, psychedelic agents, dissociative agents, psychoplastogenic or plasticity-inducing agents, monoaminergic agents, serotonergic agents, monoamine oxidase inhibitors, nootropic and pro-cognitive agents, sedative or calming agents, stimulant or wake-promoting agents, cannabinoids, terpenes, and vitamins. In embodiments, the one or more additional active compounds are selected from the group consisting of alpha lipoic acid, acetyl-L-carnitine, N-acetylcysteine, magnesium, zinc, vitamin C, vitamin E, nicotinamide, melatonin, omega-3-fatty acids, Co-Q10, 5-hydroxytryptophan, epigallocatechin gallate, and electrolytes.

[0047]

[0033] In another aspect, provided is a method of treating a medical condition in a subject, comprising administering to the subject the complex of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof; or the pharmaceutical composition of any of the disclosed embodiments.

[0048]

[0034] In embodiments, the medical condition is a disease or disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission, dopaminergic neurotransmission, or noradrenergic neurotransmission.

[0049]

[0035] In embodiments, the medical condition is a mental, behavioral, or neurodevelopmental disorder. In embodiments, the medical condition is a neurodevelopmental disorder, schizophrenia or another primary psychotic disorder, catatonia, a mood disorder, an anxiety or fear-related disorders, an obsessive-compulsive or related disorder, a disorder specifically associated with stress, a dissociative disorder, a feeding or eating disorder, an elimination disorder, a disorder of bodily distress or bodily experience, a disorder due to substance use or addictive behavior, an impulse control disorder, a disruptive behavior or dissocial disorder, a personality disorder, a paraphilic disorder, a factitious disorder, a neurocognitive disorder, a mental or behavioral disorder associated with pregnancy, childbirth or the puerperium, a sleep-wake disorder, or a sexual dysfunction. 2025-12-15

[0036] In embodiments, the complex is administered together with one or more sessions of psychotherapy.

[0050]

[0037] In embodiments, administration of the complex results in reduced adverse effect incidence or severity, as compared to administration of a comparator. In embodiments, the reduction in adverse effect incidence or severity comprises a reduction in the incidence or severity of any of inflammation, immunosuppression, oxidative stress, mitochondrial dysfunction, overall toxicity, neurotoxicity, cardiotoxicity, and renal toxicity. In embodiments, the reduction in adverse effect incidence or severity comprises a reduction in the incidence or severity of oxidative stress. In embodiments, the comparator is 3,4-methylenedioxymethamphetamine (MDMA).

[0051]

[0038] In another aspect, provided is a method of manufacturing the complex of any of the disclosed embodiments, comprising contacting a metal-containing precursor with the one or more pharmacologically active agents under reaction conditions suitable to form one or more coordinating interactions between the metal and the one or more pharmacologically active agents. In embodiments, the reaction conditions comprise solution-phase complexation conditions, hydrothermal conditions, solvothermal conditions, or mechanochemical conditions.

[0052]

[0039] Also provided is the complex of any of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in treating a medical condition in a subject.

[0053]

[0040] Also provided is the pharmaceutical composition of any of the disclosed embodiments, for use in treating a medical condition in a subject.

[0054]

[0041] Also provided is the use of the complex of any of the disclosed embodiments, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a medicament for treating a medical condition in a subject.

[0055]

[0042] Also provided is the use of the pharmaceutical composition of any of of the disclosed embodiments, for the manufacture of a medicament for treating a medical condition in a subject.

[0056]

[0043] The foregoing has outlined broadly and in summary certain pertinent features of the disclosure so that the detailed description of the invention that follows may be better understood, and so that the present contribution to the art can be more fully appreciated. Hence, this summary is to be considered as a brief and general synopsis of only some of the objects and embodiments disclosed herein, is provided solely for the benefit and convenience of the reader, and is not intended to limit in any manner the scope, or range of equivalents, to which the claims are lawfully entitled. Additional features of the invention are described hereinafter. It should be appreciated by those in the art that all disclosed specific compositions and methods are only exemplary, and may be readily utilized as a basis for modifying or designing other compositions and methods for carrying out the same purposes. Such equivalent compositions and methods will be appreciated to be also within the scope and spirit of the invention as set 2025-12-15 forth in the claims. It also will be appreciated that headings within this document are being utilized only to expedite its review by a reader. They should not be construed as limiting the invention in any manner.

[0057] BRIEF DESCRIPTION OF THE FIGURES

[0058]

[0044] To further clarify various aspects of the invention, a more particular description is rendered by reference to certain exemplary embodiments illustrated in the figures. It will be appreciated that these figures depict only illustrated embodiments of the invention and should not be considered limiting of its scope. Certain aspects of the invention are therefore further described and explained with additional specificity and detail, but still by way of example only, with reference to the accompanying figures in which:

[0059]

[0045] FIG. 1 shows mass spectrometric (MS) analysis of the exemplary active agent 2-amino- / V-[1-(1,3-benzodioxol-5-yl)propan-2-yl]-A / ,3-dimethylbutanamide (MDMA-Val);

[0060]

[0046] FIG. 2 shows MS analysis of the exemplary complex [Zn(MDMA-Val)2(H2O)2];

[0061]

[0047] FIG. 3 shows MS analysis of the exemplary complex [Fe(MDMA-Val)2(H2O)2];

[0062]

[0048] FIG. 4 shows MS analysis of the exemplary complex [Mn(MDMA-Val)2(H2O)2];

[0063]

[0049] FIG. 5 shows MS analysis of the exemplary complex [Ni(MDMA-Val)2];

[0064]

[0050] FIG. 6 shows the MS analysis of the exemplary complex [Cu(MDMA-Val)2(H2O)2].

[0065] DETAILED DESCRIPTION OF THE INVENTION

[0066]

[0051] While various aspects and features of certain embodiments are summarized above, the following detailed description illustrates several exemplary embodiments in further detail to enable one of skill in the art to practice such embodiments, and to make and use the full scope of the invention claimed. The described examples are provided for illustrative purposes and are not intended to limit the scope of the invention or its applications. The scope of the invention includes all embodiments and formulations thereof, not only those expressly described below, and it will be understood that many modifications, substitutions, changes, and variations in the described examples, embodiments, applications, and details of the invention illustrated herein can be made by those skilled in the art without departing from the spirit of the invention, or the scope of the invention as described in the claims.

[0067] A. General Definitions and Terms

[0068]

[0052] Unless defined otherwise, all technical and scientific terms herein have the meaning as commonly understood by one having ordinary skill in the art to which this invention belongs (“one of skill”). Generally, the nomenclature used and procedures performed herein are those known in fields relating to one or more aspects of the invention, e.g., biology, pharmacology, neuroscience, inorganic chemistry, bioorganic chemistry, bioinorganic chemistry, organic chemistry, synthetic chemistry, and / or medicinal chemistry, and that will be well known and commonly employed in such fields. Standard techniques and procedures will be those generally performed according to conventional methods in the art. Specific definitions to assist in understanding the embodiments are below and throughout; however, such 2025-12-15 definitions are for the purpose of describing particular embodiments, and are not intended to limit the scope of the invention.

[0069]

[0053] The singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, “an active agent” includes reference to a combination of two or more active agents, and reference to “an excipient” includes reference to a combination of two or more excipients. While the term “one or more” may be used, its absence (or its replacement by the singular “a” or “an”) does not signify the singular only, but simply provides emphasis to the possibility of multiple agents or ingredients in some particular embodiments.

[0070]

[0054] “In embodiments” is equivalent to, and used only as shorthand for, “in some embodiments.”

[0071]

[0055] “Or” means, and is interchangeable with, “and / or” unless context clearly indicates otherwise.

[0072]

[0056] The terms “comprising,” “including,” “such as,” and “having” are inclusive and not exclusive (i.e., they do not limit lists to recited elements), and are interchangeable with the phrase “including but not limited to.”

[0073]

[0057] Numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. Numerical values in some embodiments may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.

[0074]

[0058] Unless otherwise indicated, all numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, should be understood as being modified in some instances by the term “about,” even where not so stated explicitly. In alternative embodiments, such numbers should be understood as not being modified by the term “about.” In embodiments, the numerical parameters are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In embodiments, “about” refers to plus or minus five percent (±5%) of the recited unit of measure. In embodiments, “about” refers to plus or minus ten percent (±10%) of the recited unit of measure. Where “about” is used to modify one number in a series or range, it should be understood to modify all numbers in the series or range, including, for a range, both the upper and lower bounds of the range. Thus, the term “about 1, 2, or 3” is understood to mean “about 1, about 2, or about 3” and the term “about 1 to 10” means “about 1 to about 10.” The term “substantially,” where it is used to modify a feature or limitation herein, must be read in the context of the invention and in light of the knowledge in the art to provide the appropriate certainty, such as by using a standard recognized in the art for measuring the meaning of “substantially” as a term of degree, or by ascertaining the scope as would one of skill in the art. 2025-12-15

[0059] The terms “coordinate” and “coordination” refers to the interaction or binding between a ligand (e.g., comprising one or more heteroatoms from a pharmacologically active agent) and a metal center, wherein the ligand donates a pair of electrons to the metal, resulting in a bonding interaction. Coordination includes chelation, wherein a ligand forms multiple bonds with a single metal center; bridging, wherein a ligand connects two or more metal atoms; and any other mode of ligand attachment that results in the formation of a stable complex. Coordination encompasses all possible geometrical arrangements and coordination numbers, regardless of the oxidation state, electronic configuration, or the nature of the metal and ligand involved. In embodiments herein, coordinating interactions between a metal and a ligand may be depicted with solid bond lines, but as will readily be understood by one of skill, the coordinating interaction may be ionic, covalent, coordinate covalent (e.g., dative), σ-type, π-type (including back-bonding interactions), multiple bonding (e.g., a metal-ligand double- or triple-bond), or any other type of binding interaction; regardless of how the bond line is depicted in any particular structure.

[0075]

[0060] The phrases “coordination complex,” “metal-drug coordination complex,” “metal-drug complex” (and simply “complex” as shorthand) refer to a pharmacologically active agent bound to a metal center, such as a metal ion (“metal” as shorthand), through one or more coordinating interactions. A “complex” as used herein is distinct from a simple salt of the pharmacologically active agent. The key distinction of importance for pharmacologically active agents is that the molecular structure of a “complex” remains substantially intact upon dissolution with a steady-state concentration determined by equilibria.

[0076]

[0061] The term “complex” is appropriately defined in Shriver & Atkins. Shriver & Atkins' Inorganic Chemistry, Oxford University Press, Oxford, UK (p. 211): “The term complex means a central metal atom or ion surrounded by a set of ligands. A ligand is an ion or molecule that can have an independent existence... A complex is a combination of a Lewis acid (the central metal atom) with a number of Lewis bases (the ligands). The atom in the Lewis base ligand that forms the bond to the central atom is called the donor atom, because it donates the electrons used in bond formation.” Separately, an ionic bond in a salt is defined as: “The extreme case of a polar covalent bond, a covalent bond formed by an electron pair that is unequally shared by the two atoms, is an ionic bond in which one atom gains complete control over the electron pair” (id. at p. 89). Therefore, the structure, shape, and reactivity of a “complex” will be retained in solution, whereas a “salt” will dissociate in solution into separate species with individual shapes and reactivity.

[0077]

[0062] “Complexes” may form part of a salt as either a cation or anion. By convention, square brackets are used to denote a complex comprising coordinating molecules connected to a metal center through coordination bonds (also termed “dative” or “covalent” which can be further qualitatively described as having a or IT character and more accurately described through molecular orbital theory or quantum chemistry calculations). For example [Co(III)(NH3)6]3+denotes a coordination complex, which will remain substantially intact in solution, formed from a cobalt(lll) ion covalently bonded to 6 ammonia ligands. In 2025-12-15 contrast, a “salt” is bonded through electrostatic interactions and dissociates in solution to form independent cations and anions. For example, the salt [Co(III)(NH₃)6][NO3]3 denotes an ionic species that will dissociate into one [Co(III)(NH3)6]3+coordination complex and three [N03]’ ions.

[0078]

[0063] For purposes of defining the term “complex” as used herein, an “ionic” interaction refers to a substantially electrostatic (i.e., Coulombic) association between oppositely charged ions. Some pharmaceutical compositions contain salts of drugs wherein a charged drug species and a metallic counterion are ionically associated. For example, warfarin sodium is an anticoagulant, sold under the brand name Coumadin®, that comprises an anionic drug (deprotonated warfarin, which comprises a phenolate anion) in ionic association with a cationic counterion (Na+). The sodium ion and phenolate ion are dissociated in solution; these and analogous examples are not considered “complexes” herein.

[0079]

[0064] By contrast, a “non-ionic” interaction or “non-ionic coordinating” interaction refers to an association between two species, such as a metal and a ligand, each of which may be charged or uncharged, that is characterized by the substantial sharing of electrons between the species. Such interactions are as conventionally characterized in the fields of inorganic chemistry and coordination chemistry, and include covalent, coordinate covalent, σ-type, π-type, Lewis acid-base, and metal-ligand double- or triple-bond interactions. Although certain non-ionic interactions may exhibit partially ionic or electrostatic character (resulting from, e.g., charge distribution, electronegativity differences, polarization), such interactions are considered non-ionic for purposes of this disclosure.

[0080]

[0065] Complexes can be empirically differentiated from salts based on physiochemical and / or spectroscopic properties. Methods for distinguishing between ionic and non-ionic interactions include theoretical and experimental methods known to those of skill in the art. For example, one theoretical method calculates the difference in electronegativity between interacting species; a large electronegativity difference indicates an ionic interaction, whereas a smaller difference indicates a non-ionic interaction. In embodiments, an “ionic” interaction is an interaction involving the association of two species having a difference in electronegativity of at least 1.7, 1.8, 1.9, 2.0, or 2.1 units. Experimental methods include spectroscopic techniques (e.g., nuclear magnetic resonance, infrared, Raman, UV-visible) for measuring electronic or vibrational transitions that are characteristic of specific non-ionic interactions; conductivity measurements (e.g., measuring dissociation of ionic species in solution); X-ray crystallography can be used to determine the location of electron density in a molecular structure and distinguish between a coordination bond in a complex (where electron density is shared between the metal ion and the ligand and bond lengths between metal ion and ligand are typically shorter than ionic radii) in comparison to an ionic bond (where electron density is located on the separate cation and anion and bond lengths between cation and anion are at or beyond the ionic radii); thermal analysis techniques which measure bond strength; and other techniques known to those of skill. 2025-12-15

[0066] It should be understood that any embodiment referring to the administration or use of a disclosed complex should also be interpreted to encompass the administration or use of a pharmaceutical composition comprising the complex, or a pharmaceutically acceptable salt, stereoisomer, isotopolog, or solvate thereof, unless explicitly stated otherwise.

[0081]

[0067] “Alkyl” will be understood to include straight or branched radicals having any degree or level of saturation, i.e., groups having exclusively single carbon-carbon bonds, groups having one or more double carbon-carbon bonds, groups having one or more triple carbon-carbon bonds and groups having mixtures of single, double and triple carbon-carbon bonds. Where a specific level of saturation is intended, the expressions “alkanyl,” “alkenyl,” and “alkynyl” can also be used. In embodiments, an alkyl group comprises from 1 to 10 carbon atoms, from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, or from 1 to 3 carbon atoms. For any alkyl, the alkyl may be optionally substituted at one or more positions by deuterium, halogen, alkyl, alkenyl, alkynyl, alkyl ester, hydroxy, alkoxy, carboxy, formyl, aryl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryloxy, heterocyclyl, amino, alkylamino, arylamido, alkylamido, thiol, thioalkyl, thioaryl, alkylsulfonyl, alkylcarbamoyl, aryl- carbamoyl, nitro, cyano, nitrate, — OP(O)(OH)2, — OC(O)H, — OSO2OH, — OC(O)NH2, and — SONH2. In embodiments, an alkyl group will be optionally substituted. In embodiments, an alkyl group will be substituted at one or more positions. In embodiments, an alkyl group will be substituted at two or more positions, including three or more, four or more, five or more, or six or more positions. In embodiments, an alkyl group will be substituted at every position. In embodiments, an alkyl group will not be substituted at any positions.

[0082]

[0068] “Alkylene” refers to a saturated or unsaturated bivalent hydrocarbon chain having the number of carbon atoms specified (e.g., C1-C10alkylene means a saturated or unsaturated bivalent hydrocarbon chain having between one and ten carbon atoms, inclusive). An alkylene can be linear (i.e., unbranched) or branched. In embodiments, an alkylene comprises between 1 and 20 carbon atoms (i.e., a “CpC alkylene”), 1 and 10 carbon atoms (i.e., a “CpC™ alkylene”), 1 and 8 carbon atoms (i.e., a “CpCg alkylene”), 3 and 10 carbon atoms (i.e., a “C3-C10alkylene”), 3 and 8 carbon atoms (i.e., a “C3-C8alkylene”), 1 and 6 carbon atoms (i.e., a “C1-C6alkylene”), 1 and 5 carbon atoms (i.e., a “CpCs alkylene”), or 1 and 4 carbon atoms (i.e., a “C^ alkylene”). In embodiments, an alkylene comprises greater than 20 carbon atoms. Examples of alkylene include methylene (i.e., -CH2-), ethylene (i.e., -CH2CH2-), ethenylene (i.e., vinylene; -CH=CH-), ethynylene (i.e., -C=C-), propylene (i.e., -CH2CH2CH2--CH(CH3)CH2-, -CH2CH(CH3)-), propenylene, propynylene, butylene, butenylene, butynylene, and the like, including all positional and geometric isomers thereof. An alkylene can be substituted or unsubstituted.

[0083]

[0069] “Aryl” refers to a monovalent aromatic hydrocarbon radical derived by the removal of one hydrogen atom from a single carbon atom of a parent aromatic ring system. Typical aryl groups include groups derived from aceanthrylene, acenaphthylene, acephenanthrylene, anthracene, azulene, benzene, chrysene, coronene, fluoranthene, fluorene, hexacene, hexaphene, hexalene, as-indacene, s-indacene, 2025-12-15 indane, indene, naphthalene, octacene, octaphene, octalene, ovalene, penta-2,4-diene, pentacene, pentalene, pentaphene, perylene, phenalene, phenanthrene, picene, pleiadene, pyrene, pyranthrene, rubicene, triphenylene, trinaphthalene, and the like. In embodiments, an aryl group comprises from 6 to 20 carbon atoms, or between 6 to 12 carbon atoms. An aryl group can be substituted or unsubstituted.

[0084]

[0070] “Cycloalkyl” refers to a saturated monocyclic, bicyclic, fused bicyclic or bridged polycyclic ring assembly containing from 3 to 12 ring atoms, or the number of atoms indicated. Cycloalkyl can include any number of carbons, such as 3 to 6 carbon atoms, 4 to 6 carbon atoms, 5 to 6 carbon atoms, 3 to 8 carbon atoms, 4 to 8 carbon atoms, 5 to 8 carbon atoms, 6 to 8 carbon atoms, 7 to 8 carbon atoms, 3 to 9 carbon atoms, 4 to 9 carbon atoms, 5 to 9 carbon atoms, 6 to 9 carbon atoms, 7 to 9 carbon atoms, 8 to 9 carbon atoms, 3 to 10 carbon atoms, 4 to 10 carbon atoms, 5 to 10 carbon atoms, 6 to 10 carbon atoms, 7 to 10 carbon atoms, 8 to 10 carbon atoms, 9 to 10 carbon atoms, 3 to 11 carbon atoms, 4 to 11 carbon atoms, 5 to 11 carbon atoms, 6 to 11 carbon atoms, 7 to 11 carbon atoms, 8 to 11 carbon atoms, 9 to 11 carbon atoms, 10 to 11 carbon atoms, 3 to 12 carbon atoms, 4 to 12 carbon atoms, 5 to 12 carbon atoms, 6 to 12 carbon atoms, 7 to 12 carbon atoms, 8 to 12 carbon atoms, 9 to 12 carbon atoms, 10 to 12 carbon atoms, and 11 to 12 carbon atoms. Monocyclic cycloalkyl rings include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. Bicyclic compounds include spirocyclic compounds, fused bicyclic compounds and bridged bicyclic compounds. Bicyclic and polycyclic cycloalkyl rings include, for example, norbornane, bicyclooctane, decahydronaphthalene and adamantane. When cycloalkyl is a monocyclic C3.8cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. When cycloalkyl is a monocyclic C3.6cycloalkyl, exemplary groups include, but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. Cycloalkyl groups can be substituted or unsubstituted.

[0085]

[0071] “Halogen” refers to fluorine, chlorine, bromine, and iodine.

[0086]

[0072] “Heterocycloalkyl” refers to a cycloalkyl as defined above, having from 3 to 12 ring members and from 1 to 4 heteroatoms of N, O and S. Heterocycloalkyl includes bicyclic compounds which include a heteroatom. Bicyclic compounds includes spirocyclic compounds, fused bicyclic compounds, and bridged bicyclic compounds The heteroatoms can also be oxidized, such as, but not limited to, — S(O)— and — S(O)2—. Heterocycloalkyl groups can include any number of ring atoms, such as, 3 to 6, 4 to 6, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heterocycloalkyl groups, such as 1, 2, 3, or 4, or 1 to 2, 1 to 3, 1 to 4, 2 to 3, 2 to 4, or 3 to 4. The heterocycloalkyl group can include groups such as aziridine, azetidine, pyrrolidine, piperidine, azepane, azocane, quinuclidine, pyrazolidine, imidazolidine, piperazine (1,2-, 1,3-and 1,4-isomers), oxirane, oxetane, tetrahydrofuran, oxane (tetrahydropyran), oxepane, thiirane, thietane, thiolane (tetrahydrothiophene), thiane (tetrahydrothiopyran), oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, dioxolane, dithiolane, morpholine, thiomorpholine, dioxane, or dithiane. The 2025-12-15 heterocycloalkyl groups can also be fused to aromatic or non-aromatic ring systems to form members including, but not limited to, indoline. Heterocycloalkyl groups can be unsubstituted or substituted. For example, heterocycloalkyl groups can be substituted with Cr6alkyl or oxo (=0), among many others.

[0087]

[0073] “Heteroaryl” refers to a monocyclic or fused bicyclic or tricyclic aromatic ring assembly containing 5 to 16 ring atoms, where from 1 to 5 of the ring atoms are a heteroatom such as N, 0 or S. Heteroaryl groups can include any number of ring atoms, such as, 5 to 6, 3 to 8, 4 to 8, 5 to 8, 6 to 8, 3 to 9, 3 to 10, 3 to 11, or 3 to 12 ring members. Any suitable number of heteroatoms can be included in the heteroaryl groups, such as 1, 2, 3, 4, or 5, or 1 to 2, 1 to 3, 1 to 4, 1 to 5, 2 to 3, 2 to 4, 2 to 5, 3 to 4, or 3 to 5. Heteroaryl groups can have from 5 to 8 ring members and from 1 to 4 heteroatoms, or from 5 to 8 ring members and from 1 to 3 heteroatoms, or from 5 to 6 ring members and from 1 to 4 heteroatoms, or from 5 to 6 ring members and from 1 to 3 heteroatoms. A heteroaryl includes groups such as pyrrole, pyridine, imidazole, pyrazole, triazole, tetrazole, pyrazine, pyrimidine, pyridazine, triazine (1,2,3-, 1,2,4- and 1,3,5-isomers), thiophene, furan, thiazole, isothiazole, oxazole, and isoxazole. The heteroaryl groups can also be fused to aromatic ring systems, such as a phenyl ring, to form members including, but not limited to, benzopyrroles such as indole and isoindole, benzopyridines such as quinoline and isoquinoline, benzopyrazine (quinoxaline), benzopyrimidine (quinazoline), benzopyridazines such as phthalazine and cinnoline, benzothiophene, and benzofuran. Other heteroaryl groups include heteroaryl rings linked by a bond, such as bipyridine. Heteroaryl groups can be substituted or unsubstituted.

[0088]

[0074] “Acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, or heterocyclyl, connected via a carbonyl group as a substituent. Examples include formyl, acetyl, propanoyl, benzoyl, and acryl. An acyl may be substituted or unsubstituted.

[0089]

[0075] “Hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3-hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.

[0090]

[0076] “Haloalkoxy” refers to an — O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy). The halogens may be the same or different in each instance. Such groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy and 2-fluoroisobutoxy. A haloalkoxy may be substituted or unsubstituted.

[0091]

[0077] “Alkylthio” refers to the formula —SR, wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, or heterocyclyl, as defined herein. Exemplary alkylthio groups include methylthio, ethylthio, n-propylthio, isopropylthio, n-butylthio, iso-butylthio, sec-butylthio, phenylthio, and benzylthio. An alkylthio may be substituted or unsubstituted. 2025-12-15

[0078] “Thioalkyl” refers to the formula — RA-S-RB, wherein RAis alkylene as defined herein, and RBis an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, or heterocyclyl, as defined herein.

[0092]

[0079] “Aminoalkyl” refers to a univalent alkyl group in which one or more of the hydrogen atoms are replaced by an amino group. Each amino group can be a primary, secondary, or tertiary amine, or a quaternary ammonium. Examples of aminoalkyl groups include aminomethyl, aminoethyl, 2-aminoethyl, 3-aminopropyl, N-methylaminoethyl, and N, N-dimethylaminopropyl. An aminoalkyl group can be substituted or unsubstituted.

[0093]

[0080] “Carboxyalkyl” refers to a univalent alkyl group in which one or more of the hydrogen atoms are replaced by a carboxy or carboxylic acid group. Example carboxyalkyl groups include carboxymethyl, carboxyethyl, carboxypropyl, etc. A carboxyalkyl may be substituted or unsubstituted.

[0094]

[0081] “O-carboxy” refers to a — RC(=O)O— group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carboxy may be substituted or unsubstituted.

[0095]

[0082] “Ester” and “C-carboxy” refer to a — C(=O)OR group in which R can be the same as defined with respect to O-carboxy. Ester and C-carboxy groups may be substituted or unsubstituted.

[0096]

[0083] “Oxo” refers to =0.

[0097]

[0084] “O-carbamyl” refers to a — OC(=O)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An O-carbamyl may be substituted or unsubstituted.

[0098]

[0085] “N-carbamyl” refers to an ROC(=O)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-carbamyl may be substituted or unsubstituted.

[0099]

[0086] “Amido” refers to C-amido and N-amido. A “C-amido” group refers to a — C(=O)N(RARB) group in which RAand RBcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. A C-amido may be substituted or unsubstituted. “N-amido” refers to a RC(=O)N(RA)— group in which R and RAcan be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, or heterocyclyl, as defined herein. An N-amido may be substituted or unsubstituted.

[0100]

[0087] “Optionally substituted” unless otherwise specified means that a group may be unsubstituted, or substituted by one or more of the substituents listed for that group. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. When there are more than one substituents, the substituents may be the same or different. In one embodiment, an optionally substituted group has one substituent. In another embodiment, an optionally substituted group has two substituents. In another 2025-12-15 embodiment, an optionally substituted group has three substituents. In another embodiment, an optionally substituted group has four substituents. If no substituents are indicated for an “optionally substituted” or “substituted” group, it is meant that the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl), (heterocyclyl)alkyl, hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amino group, a di-substituted amino group, and a tri-substituted amino group.

[0101]

[0088] A comprehensive list of the abbreviations utilized by organic chemists of ordinary skill in the art appears in the first issue of each volume of the Journal of Organic Chemistry; this list is typically presented in a table entitled Standard List of Abbreviations; the current list as of the date of this filing is hereby incorporated by reference as if fully set forth herein.

[0102]

[0089] Additional definitions and abbreviations are provided elsewhere herein.

[0103] B. Metal-Drug Complexes

[0104]

[0090] In one aspect, provided are metal-drug coordination complexes comprising: (a) a pharmacologically active agent; and (b) a metal center (e.g., a metal ion); wherein the pharmacologically active agent is coordinated to the metal center.

[0105] a. Active Agents

[0106]

[0091] In one aspect, provided are metal-drug complexes comprising a pharmacologically active agent. The term “pharmacologically active agent” may be used interchangeably with “drug” or “pharmacologically active compound”, and simply “active agent” as shorthand, and refers generally and without limitation to any compound that can trigger, either directly or indirectly, a physiological response when administered to a subject, such as a therapeutic response.

[0107]

[0092] A “physiological response” includes any measurable or observable effect on a biological system at the molecular, cellular, tissue, organ, or organismal level, including modulation of receptor or transporter activity, alteration of neurotransmitter release or uptake, modulation of signaling pathways, effects on metabolism, and changes in behavior, cognition, or perception. A “therapeutic response” or, equivalently, a “therapeutic effect” refers to any beneficial or desired effect in a subject, including antioxidant, anti-inflammatory, neuroprotective, anxiolytic, antidepressant, anti-PTSD, antineuropathic, antinociceptive, analgesic, antimigraine, empathogenic, psychedelic, entactogenic, and / or stimulant effect. Such effects may be characterized as “therapeutic” regardless of whether they occur in a clinical context of treating a medical condition, or in a non-clinical, non-medical, context in which a beneficial effect is desired. 2025-12-15

[0093] In embodiments, an active agent directly exerts a pharmacological effect, such as by directly interacting with one or more biological targets (e.g., receptors, transporters) to induce a physiological response. In other embodiments, an active agent is substantially inactive at such targets but indirectly induces a physiological response, such as by acting as a prodrug that undergoes one or more chemical or enzymatic transformations in vivo to generate a compound that directly exerts a pharmacological effect.

[0108]

[0094] In embodiments, the active agent is a phenethylamine. As will be readily understood by those in the art, phenethylamines are compounds having the general structure of Formula (A), wherein RN1, RN2, R°, Rp, and each of R2-R6are as taught herein and as generally understood in the art:

[0109] N

[0110]

[0111]

[0095] In embodiments, RN1, RN2, R°, Rp, and each of R2-R6are independently hydrogen, deuterium, halogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocyclyl, amino acid, or ligand moiety. In embodiments, R3and R4are joined together to form an optionally substituted heterocyclyl, such as a dioxole (as with MDMA), a furan, a tetrahydrofuran, a thiophene, a pyrrole, a pyridine, a pyrrolidine, an ethylene oxide, an ethylenimine, a trimethylene oxide, a pyran, a piperidine, an imidazole, a thiazole, a dioxane, a morpholine, or a pyrimidine. In embodiments, R3and R4are joined together to form an optionally substituted aryl, such as a phenyl, or an optionally substituted heteroaryl. In embodiments, the phenethylamine comprises a quaternary ammonium cation wherein each of RN1, RN2, and an additional RN3are independently an alkyl group or an aryl group, and with all other substituents as above. In embodiments, the phenethylamine is a quaternary salt, in which an additional RN3is connected to the nitrogen to which RN1and RN2are bound; wherein RN3is optionally substituted alkyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted heterocyclyl.

[0112]

[0096] In embodiments, the active agent is a phenethylamine is a compound of Formula (A) wherein one of RN1and RN2is H. In embodiments, both of RN1and RN2are H. In embodiments, one of RN1and RN2is C1-C6alkyl, and the other of RN1and RN2is H. In embodiments, one of RN1and RN2is methyl, and the other of RN1and RN2is H. 2025-12-15

[0097] In embodiments, the active agent is a phenethylamine selected from the group consisting of mescaline, a-ethylmescaline, escaline, symbescaline, metaescaline, allylescaline, methallylescaline, asymbescaline, cyclopropylmescaline, phenescaline, 4-desoxymescaline, isomescaline, proscaline, metaproscaline, isoproscaline, thiomescaline, thioescaline, thioproscaline, thiobuscaline, a thiomescaline analog (e.g., 3-TM, 4-TM), buscaline, a thioisomescaline (e.g., 2-TIM, 3-TIM, 4-TIM), Aleph (i.e., DOT), a thiometaescaline (e.g., 3-TME, 4-TME, 5-TME), a thiotrisescaline (e.g., 3-T-TRIS, 4-T-TRIS), a thiosymbescaline (e.g., 3-TSB, 4-TSB), Aleph-2, Aleph-4, Aleph-6, Aleph-7, Ariadne, Beatrice (i.e., MDO-D, MDOM), BIS-TOM, BOB, BOD, BOH, BOHD, BOM, 4-Br-3,5-DMA, 2-Br-4,5-MDA, MDEA, 3C-BZ, a 2C-X compound (e.g., 2C-B, 2C-B-AN, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-B-FLY-NB0Me, 2C-B-FLY-NB2EtO5CI, 2C-Bn, 2C-Bu, 2C-B-5-hemiFLY, 20-0, 2C-C-3, 2C-CN, 2C-CP, 2C-D, 2C-E, 2C-EF, 2C-F, 2C-G, 2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, 2C-G-N, 2C-H, 2C-I, 2CB-lnd, 2C-iP, 2C-N, 2C-NH2, 2C-PYR, 2C-PIP, 20-0, 2C-O-4, 2C-M0M, 2C-P, 2C-Ph, 2C-Se, 2C-T, 2C-T-2, 2C-T-3, 2C-T-4, 2C-T-5, 2C-T-6, 2C-T-7, 2C-T-8, 2C-T-9, 2C-T-10, 2C-T-11, 2C-T-12, 2C-T-13, 2C-T-14, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-18, 2C-T-19, 2C-T-21, 2C-T-21.5, 2C-T-22, 2C-T-23, 2C-T-24, 2C-T-25, 2C-T-27, 2C-T-28, 2C-T-30, 2C-T-31, 2C-T-32, 2C-T-33, 2C-DFM, 2C-TFM, 2C-TFE, 2C-YN, 2C-V, 2C-AL, CPM, psi-2C-T-4, 2C-Se), 3C-BZ, 3C-E, 4-D, beta-D, 2,4-DMA, 2,5-DMA, 3,4-DMA, DMCPA, DME, DMMDA, DMMDA-2, DMPEA, DOAM, DOB, DOBU, DOC, DOEF, DOET, DOI, DOM (i.e., STP), psi-DOM, DON, DOPR, EEE, EEM, EME, EMM, ETHYL-J, ETHYL-K, F-2, F-22, FLEA, Ganesha, a GANESHA analog (e.g., G-3, G-4, G-5, G-N), HOT-2, HOT-7, HOT-17, IDNNA, IRIS, BDB, Lopophine, 4-MA (i.e., PMA), MADAM-6, MDA, MDMA, MDAL, MDBU, MDBZ, MDCPM, MDDM, MDE, MDHOET, MDIP, MDMC, MDMEO, MDMEOET, MDMP, MDOH, MDPEA, MDPH, MDPL, MDPR, MEDA, MEE, MEM, MEPEA, META-DOB, META-DOT, METHYL-DMA, METHYL-DOB, METHYL-J (i.e., MBDB), METHYL-K, METHYL-MA (i.e., PMMA), METHYL-MMDA-2, MMDA, MMDA-2, MMDA-3a, MMDA-3b, MME, MPM, ORTHO-DOT, PEA, PROPYNYL, tetramethoxyamphetamine, 3-TASB, 4-TASB, 5-TASB, 3-TE, 4-TE, TMA, TMA-2, TMA-3, TMA-4, TMA-5, TMA-6, 2T-MMDA-3a, 4T-MMDA-2, TMPEA, 2-TOET, 5-TOET, 2-TOM, 5-TOM, TOMSO, 4-MTA, MDAI, 5-methyl-MDA, 5-APB, 6-APB, and DiFMDA.

[0113]

[0098] Phenethylamines can be synthesized according to known procedures (see, e.g., Shulgin & Shulgin. 1992. PiHKAL. A chemical love story, Transform Press, Berkeley, CA; Glennon et al. 1986. J Med Chem., 29(2), 194-199; Nichols et al. 1991. J Med Chem., 34(1), 276-281; Trachsel et al. Chem Biodivers.

[0114] 2006;3:326-336); and references cited therein), with necessary adaptations and modifications being that known and understood to those of ordinary skill.

[0115]

[0099] In embodiments, the active agent is MDMA. MDMA can be synthesized by various known synthetic routes, including the Leuckart reaction (A), reductive amination of a ketone intermediate with methylamine (B), and amination of a precursor with a suitable leaving group (C): 2025-12-15

[0116]

[0117] X ~ CLBr, OTs, ete.

[0118]

[0100] These and other suitable synthetic methods are known to those of skill in the art, for example as disclosed in Shulgin AT. J. Psychoact. Drugs. 1986;18:291-304; Nair et al. ACS Omega.

[0119] 2022;7(1):900-907; Sherwood et al. ACS Omega. 2023;8(24):22132-22137.

[0120]

[0101] In embodiments, the active agent has the structure of:

[0121] R2RpRNI

[0122]

[0123] wherein L is H or a ligand moiety, and RN1, R°, Rp, and each of R2-R6are as defined for Formula (A).

[0124]

[0102] In embodiments, the active agent has the structure of Formula (I),

[0125]

[0126] wherein L is H or a ligand moiety.

[0127] b. Ligand Moieties

[0128]

[0103] In embodiments, the active agent of a disclosed metal-drug complex comprises a ligand moiety. A “ligand moiety” generally refers to a molecular fragment that can coordinate to a metal (e.g., a metal ion), typically through one or more heteroatoms (e.g., N, O, S), although other coordination modes are also contemplated. For example, a ligand moiety may coordinate to a metal via π-coordination; thus, haptic ligands (e.g., η2, η3, η4, η5, η6) are also included in the disclosure. Non-limiting examples of ligand moieties include amino acids, amines, carboxylates, thiols, hydroxyls, and other heteroatom-containing substituents and functional groups, each of which may be optionally substituted; as well as substituents 2025-12-15 and functional groups having one or more π-bonds and / or delocalized π-electron systems available for coordination, such as alkenyl, cycloalkenyl, aryl, heteroaryl, etc. each of which may also be optionally substituted.

[0129]

[0104] In embodiments, the chemical bond connecting the ligand moiety to the active agent (i.e., the N-L bond shown in Formula (A) or (I)) can be hydrolyzed (e.g., replacing N-L with N-H) in vivo. Such hydrolysis may occur enzymatically (e.g., mediated by the action of endogenous hydrolyase enzymes, for instance amidases and esterases) or non-enzymatically (e.g., spontaneously at physiological pH, or at the pH of the gastrointestinal tract (e.g., stomach, intestines, etc.)). Thus, without being bound by theory, the ligand moiety may serve at least two functions: (1) increasing the number of coordination sites of the active agent to improve its binding to the metal; (2) acting as a promoiety that can be cleaved after administration to release the active agent in vivo.

[0130]

[0105] In embodiments, the ligand moiety comprises an amino acid. The term “amino acid” refers to naturally occurring and non-natural amino acids, as well as amino acid analogs and amino acid mimetics similar in structure to the naturally occurring amino acids. The term includes the 20 common amino acids (alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine) and pyrrolysine and selenocysteine. Amino acid analogs refers to compounds that have the same core chemical structure as a naturally occurring amino acid, i.e., an a carbon that is bound to a hydrogen, a carboxyl group, an amino group, and an R group, such as, homoserine, norleucine, methionine sulfoxide, methionine methyl sulfonium. Such analogs have modified R groups (such as, norleucine) or modified peptide backbones, but retain the same basic chemical structure as a naturally occurring amino acid. Also included are amino acids, analogs, and mimetics comprising a substituted amino group, such as an acylated (e.g., acetylated) amino group. For brevity, specific amino acids may be referred to by their commonly known three letter symbols.

[0131]

[0106] In embodiments, the ligand moiety has the structure of

[0132]

[0133] , wherein R is an amino acid side chain, R' is H or — COCH3, and * indicates the point of connection to the rest of the molecule. Hence, in some such embodiments, the active agent has the structure of

[0134]

[0135] , wherein R is an amino acid side chain, and R' is H or — COCH3; or R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl. In embodiments, R is H, unsubstituted C1-C12alkyl, C1-C6hydroxyalkyl, C1-C6thioalkyl, C1-C6aminoalkyl, or 2025-12-15 C1-C6alkyl substituted by aryl, heteroaryl, oxo, carboxylate, or amido. Such agents are referred to herein as MDMA-amino acid conjugates (MDMA-AAs).

[0136]

[0107] As will be understood by those of skill in the art, the term “amino acid side chain” refers to any substituent corresponding to the side-chain of a naturally occurring or non-naturally occurring amino acid. The term includes linear, branched, and cyclic groups; saturated and unsaturated groups; aromatic, heteroaromatic, and aliphatic groups; acidic, basic, polar, and non-polar groups; and groups comprising one or more heteroatoms (e.g., N, 0, S). Exemplary amino acid side chains include those comprised in the 20 canonical amino acids (e.g., alkyl, hydroxyalkyl, thioalkyl, aryl, heteroaryl, carboxylate, amide, guanidinium, imidazolyl, indolyl, phenolic, sulfhydryl), and non-canonical or synthetic amino acid side chains such as those disclosed in Brouwer et al. Chem Rev. 2024;124(19):10877-10923; and other references known to those of skill.

[0137]

[0108] In embodiments, R and R' are taken together with the intervening atoms to form a heterocyclyl ring (e.g., as in proline). In embodiments, R is H (e.g., as in glycine). In embodiments, R is a side chain of any natural or unnatural amino acid. In embodiments, R is alkyl (e.g., as in alanine, valine, leucine, isoleucine, etc.). In embodiments, R is a polar uncharged side chain (e.g., as in serine, threonine, asparagine, glutamine, etc.). In embodiments, R is a positively charged side chain (e.g., as in arginine, histidine, lysine, etc.). In embodiments, R is a negatively charged side chain (e.g., as in aspartic acid, glutamic acid, etc.). In embodiments, R is a sulfur-containing side chain (e.g., as in cysteine, methionine, selenocysteine, etc.). In embodiments, R is a side chain comprising an aryl or heteroaryl (e.g., as in phenylalanine, tyrosine, tryptophan).

[0138]

[0109] In embodiments, R is H, C1-C12alkyl, C1-C6hydroxyalkyl, C1-C6alkylthio, C1-C6thioalkyl, C1-C6aminoalkyl, C1-C6carboxyalkyl, C1-C6alkylene-C6-C12aryl, C1-C6alkylene— (3- to 10-membered heteroaryl), C1-C6alkylene— guanidino, C1-C6alkylene-CONH2; each of which may be optionally substituted. In embodiments, R is H. In embodiments, R is C1-C12alkyl. In embodiments, R is C1-C6alkyl. In embodiments, R is methyl. In embodiments, R is ethyl. In embodiments, R is propyl. In embodiments, R is n-propyl. In embodiments, R is isopropyl. In embodiments, R is butyl. In embodiments, R is sec-butyl. In embodiments, R is isobutyl. In embodiments, R is tert-butyl. In embodiments, R is C1-C6hydroxyalkyl. In embodiments, R is -CH2OH (i.e., hydroxymethyl). In embodiments, R is C2hydroxyalkyl (i.e., a hydroxyethyl). In embodiments, R is -CH2-CH2OH. In embodiments, R is -C(OH)H-CH3. In embodiments, R is C1-C6alkylthio. In embodiments, R is C1-C6thioalkyl. In embodiments, R is -CH2SH. In embodiments, R is -CH2-CH2-SCH3. In embodiments, R is C1-C6aminoalkyl. In embodiments, R is –(CH2)4–NH2or -(CH2)4-NH3+. In embodiments, R is C1-C6carboxyalkyl. In embodiments, R is C1-C6alkylene-COO’. In embodiments, R is -CH2-COO’. In embodiments, R is -(CH2)2-C00‘. In embodiments, R is C1-C6alkylene-COOH. In embodiments, R is -CH2-COOH. In embodiments, R is -(CH2)2-COOH. In embodiments, R is C1-C6alkylene-C6-C12aryl. In embodiments, R is C1-C6alkylene— phenyl. In 2025-12-15 embodiments, R is -CH2-phenyl. In embodiments, R is -CH2-(4-hydroxyphenyl). In embodiments, R is C1-C6alkylene— (3- to 10-membered heteroaryl). In embodiments, R is C1-C6alkylene— indolyl. In embodiments, R is —CH2— indolyl. In embodiments, R is — CH2— (3-indolyl). In embodiments, R is C1-C6alkylene— imidazolyl. In embodiments, R is —CH2— imidazolyl. In embodiments, R is — CH2— (imidazol-4-yl). In embodiments, R is C1-C6alkylene— guanidino. In embodiments, R is — (CH2)3— guanidino. In embodiments, R is C1-C6alkylene-CONH2. In embodiments, R is -CH2-CONH2. In embodiments, R is -(CH2)2-CONH2.

[0139]

[0110] In embodiments, amino acid moieties and / or atoms therein are depicted in an ionized form (e.g., protonated or deprotonated) which by convention typically reflects the ionic form present at physiological pH. However, all charged and uncharged (i.e., neutral and ionized) forms of amino acid moieties (and active agents and complexes comprising such moieties), are included in the disclosure.

[0140]

[0111] In embodiments, wherein L is a ligand moiety, the active agent has the structure of:

[0141] ex X X

[0142] < ZB?x v YNH2

[0143] ^0

[0144] (MDMA-GI) 0 o (MDMA-Ala)

[0145] ex

[0146] m u

[0147] oxx o < O' 7" XTfl “ (MDMA-Va ) (MDMA-Leu)

[0148] ,0H

[0149] I JL X

[0150] o < C°X7 * 0

[0151] (MDMA-lle (MDMA-Ser)

[0152] 0

[0153] NHz

[0154] NH2x sX.

[0155] X Y Y NH2

[0156] 5 <ox X °

[0157] (MDMA-Asr i) (MDMA-GIn)

[0158] C\X „ X X

[0159] Y J NH2

[0160] □ < X.

[0161]

[0162] (MDMA-Ph( 5) (MDMA-Tyr) 2025-12-15

[0163] (MDMA-Cys)

[0164] S' (M DM A-N-acetylcystei ne (M DM A-N AC)) (MDMA-Met)

[0165] (MDMA-Arg)

[0166] (MDMA-Lys)

[0167] (MDMA-Glu)

[0168]

[0169] (MDMA-C12) or a pharmaceutically acceptable salt, stereoisomer, or isotopolog thereof. 2025-12-15

[0112] In embodiments, the active agent is a compound disclosed in WO 2023 / 283373, WO 2022 / 053696, WO 2022 / 106947, U. S. Pat. No. 11,896,670, U. S. Pub. No. 2023 / 0227420, or U. S. Pub. No.

[0170] 2023 / 0233688, each of which is incorporated by reference as if fully set forth herein.

[0171]

[0113] In embodiments, a ligand moiety is selected for targeted drug delivery. Targeted drug delivery refers to a method of achieving a desired concentration of a drug at a site of action to produce a desired pharmacological effect while minimizing side effects. In embodiments, the ligand moiety of a disclosed metal-drug complex is a substrate for a transcellular transport pathway, such as in the mammalian brain endothelial cells (BECs) that comprise the blood-brain barrier. In embodiments, the ligand moiety increases the permeability of a drug-metal complex to the blood-brain barrier above the permeability of a comparator.

[0172]

[0114] In embodiments, the ligand moiety is an amino acid substrate for an amino acid transporter. Amino acid transporters are known to those of skill in the art, and include L-type amino acid transporter (LAT) systems, cationic amino acid (CAT) systems, System L, System X, System XG; System A, System ASC System N, System n, System Na+-LNAA, and excitatory amino acid transporter (EAATs) systems (see, e.g., Zaragoza. Front Physiol. 2020;11:973).

[0173]

[0115] In embodiments, the amino acid transporter is an L-type amino acid transporter (LAT), such as LAT1. LAT1 is a Na+- and pH-independent exchanger of large branched-chain and aromatic neutral amino acids, such as phenylalanine, leucine, isoleucine, tryptophan, histidine, and tyrosine (Puris et al. Pharm Res. 2020;37(5):88). In embodiments, the amino acid transporter is a cationic amino acid (CAA) transporter. In embodiments, the CAA transporter is cationic amino acid transporter system y+ (CAT). In embodiments, the CAT transporter is a subtype selected from the group CAT1, CAT2B, and CAT3. CAT transporters are the primary CAA transporters of the blood-brain barrier, and are selective for basic amino acids, such as lysine, arginine, and ornithine. Thus, certain complexes comprising amino acids such as lysine, arginine, and ornithine may be substrates for one or more CAT transporters. In embodiments, the CAA transporter is a broad substrate amino acid transport system (BAT). In embodiments, the BAT is a subtype selected from the group Bo +, b0 +, and y+LAT2. BAT transporters transport neutral amino acids, specifically responsible for exchanging arginine and glutamine across the cell membrane.

[0174]

[0116] In embodiments, an active agent is synthesized by amide coupling of MDMA with an amino acid or amino acid precursor (e.g., a protected amino acid) (see Example 1):

[0175]

[0176]

[0117] The formation of an amide bond is one of the most thoroughly investigated functional group transformations in all of organic chemistry (see, e.g., E. Wiinsch (Ed.), Synthese von Peptiden, vol. 2025-12-15 15, parts 1 and 2 of Houben-Weyl, Methoden der organischen Chemie, Thieme, Stuttgart, 1974; Bodanszky, M. Principles of Peptide Synthesis, Springer, Berlin, 1984; Jones, J. The Chemical Synthesis of Peptides. Clarendon Press / Oxford University Press, 1991; Okada, Y. Synthesis of Peptides by Solution Methods. Curr. Org. Chem. 2001, 5, 1-43; Aimoto, S. Contemporary Methods for Peptide and Protein Synthesis. Curr. Org. Chem. 2001, 5, 45-87). Thus, the selection of suitable reaction conditions for this step is well within the capabilities of one of ordinary skill.

[0177]

[0118] A variety of amide coupling reagents may be suitable for this process, including, for example, benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (BOP), 1 -[(1 -(cyano-2-ethoxy-2-oxoethylideneaminooxy) dimethylaminomorpholino)] uranium hexafluorophosphate (COMU), 1-[bis(dimethylamino)methylene]-1 H-1,2,3-triazolo[4,5-b] pyridinium 3-oxide hexafluorophosphate (HATU), 2-(1 H-benzotriazole-1 -yl)-1, 1,3,3-tetramethyluronium hexafluorophosphate (HBTU), O-(1 H-6-chlorobe n zotriazole- 1 -yl)-1, 1,3,3-tetramethyluronium hexafluorophosphate (HCTU), benzotriazole-1-yl-oxy-tris-pyrrolidino-phosphonium hexafluorophosphate (PyBOP®), (7-azabenzotriazol-1-yloxy), trispyrrolidinophosphonium hexafluorophosphate (PyAOP), N, N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC). In embodiments, the coupling agent is used in conjunction with an organic base (e.g., triethylamine, diisopropylethylamine).

[0178]

[0119] The amino acid precursor may be any precursor known to those of skill in the art, including a protected amino acid (i.e., an amino acid wherein one or both of the C- and N-termini are protected by a protecting group). The side chain of the amino acid precursor may also be protected. In embodiments, the amino acid precursor comprises alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, tyrosine, serine, threonine, cysteine, asparagine, glutamine, aspartic acid, glutamic acid, lysine, arginine, histidine, glycine, or proline; and optionally comprises a protecting group at the C- and / or N-terminus. Common protecting groups include tert-butyloxycarbonyl (Boc), 9-fluorenylmethyloxycarbonyl (Fmoc), benzyloxycarbonyl (Cbz), allyloxycarbonyl (Alloc), 2,2,2-trichloroethoxycarbonyl (Troc), methoxycarbonyl (Moc), 2-trimethylsilylethoxycarbonyl (Teoc), 1-(4,4-dimethyl-2,6-dioxocyclohex-1 -ylidene)ethyl (Dde), 1-(4-isovaleryl-2,6-dioxocyclohex-1-ylidene)ethyl (IvDde), trityl (Trt), 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl (Pbf), 4-methyltrityl (Mtt), tert-butyl (tBu), methyl ester (OMe), benzyl ester (OBn), and fluorenylmethyl ester (OFm). Descriptions of protecting groups and their use can be found in the literature (see, e.g., General descriptions of protecting groups can be found in the literature: Greene, T. W. Protective Groups in Organic Synthesis, John Wiley & Sons, New York, 1991; Kocienski, P. J. Protecting Groups, Thieme, Stuttgart, 2005.) The selection of suitable protecting groups and suitable reaction conditions for protection and deprotection is readily conducted by one of skill.

[0179]

[0120] In embodiments, an active agent is synthesized according to the reaction scheme below: 2025-12-15 o

[0180] B0C2O Boc O CH3NH2Boc 0 or coupling conditions (e.g., DCC. CD!)

[0181]

[0182] (then deprotection)

[0183]

[0121] Additional methods for synthesis of the active agents described herein and any necessary starting materials are either described in the art or will be readily apparent to the skilled artisan in view of general references well-known in the art (see, e.g., Green et al., “Protective Groups in Organic Chemistry,” (Wiley, 2nd ed. 1991); Harrison et al., “Compendium of Synthetic Organic Methods,” Vols. 1-8 (John Wiley and Sons, 1971-1996); “Beilstein Handbook of Organic Chemistry,” Beilstein Institute Organic Chem., Frankfurt, Germany; Feiser et al, “Reagents for Organic Synthesis,” Volumes 1-17, Wiley Interscience; Trost et al., “Comprehensive Organic Synthesis,” Pergamon Press, 1991; “Theilheimer’s Synthetic Methods of Organic Chemistry,” Vols. 1-45, Karger, 1991; March, “Advanced Organic Chemistry,” Wiley Intersci., 1991; Larock “Comprehensive Organic Transformations,” VCH Publishers, 1989; Paquette, “Encyclopedia of Reagents for Organic Synthesis,” John Wiley & Sons, 1995) and may be used to synthesize the disclosed compounds.

[0184]

[0122] In general, the approaches used for similar compounds may be used. For example, the synthesis of amino acid derivatives of MDMA disclosed in U. S. Pat. No. 11,896,670 and U. S. Pub. Nos.

[0185] 2023 / 0227420 and 2023 / 0233688 may be used, with necessary adaptations and modifications being that known and understood to those of ordinary skill.

[0186] c. Metals

[0187]

[0123] In embodiments, a disclosed metal-drug coordination complex comprises a metal center (e.g., a metal ion) coordinated to one or more molecules of an active agent.

[0188]

[0124] The metal can be any metal capable of forming a coordination complex with an active agent disclosed herein. In embodiments, the metal is capable of forming one or more coordinating interactions with an active agent. In embodiments, the metal is capable of forming one or more non-ionic coordinating interactions with an active agent. 2025-12-15

[0125] In embodiments, the metal is present in any oxidation state capable of forming a coordination interaction with an active agent. In embodiments, the metal is present in a +1, +2, +3, +4, +5, +6, +7, or higher oxidation state. In embodiments, the oxidation state of the metal is selected to provide a desired coordination environment, stability, dissociation rate, or physicochemical property of the complex. Oxidation states are designated herein using conventional inorganic chemistry nomenclature (e.g., Fe(ll), Fe(lll)), and such designations (including superscripts, such as FeII, FeIII, Fe2+, Fe3+) refer to the formal oxidation state of the metal center.

[0189]

[0126] In embodiments, the metal is a transition metal. Transition metals are as known to those of skill in the art, and include metals from groups 3-12 of the periodic table. In embodiments, the metal is a d-block metal. In embodiments, the metal is a p-block metal. In embodiments, the metal is zinc (Zn), iron (Fe), silver (Ag), cobalt (Co), copper (Cu), nickel (Ni), manganese (Mn), gold (Au), palladium (Pd), scandium (Sc), molybdenum (Mo), tungsten (W), chromium (Cr), vanadium (V), titanium (Ti), gallium (Ga), germanium (Ge), arsenic (As), selenium (Se), yttrium (Y), zirconium (Zr), niobium (Nb), technetium (Tc), ruthenium (Ru), rhodium (Rh), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), hafnium (Hf), tantalum (Ta), rhenium (Re), osmium (Os), iridium (Ir), platinum (Pt), mercury (Hg), thallium (TI), lead (Pb), or bismuth (Bi).

[0190]

[0127] In embodiments, the metal is Zn, Fe, Mn, Ni, Ag, Co, Cu, Au, Pd, Sc, Mo, W, Cr, or V.

[0191]

[0128] In embodiments, the metal is Zn(ll), Fe(ll), Fe(lll), Mn(ll), Mn(lll), Mn(IV), Mn(V), Mn(VI), Ni(ll), Ni(lll), Ag(l), Co(ll), Co(lll), Cu(l), Cu(ll), Au(l), Au(lll), Pd(ll), Sc(lll), Mo(ll), Mo(lll), Mo(IV), Mo(V), Mo(VI), W(ll), W(lll), W(IV), W(V), W(VI), Cr(ll), Cr(lll), Cr(IV), Cr(V), Cr(VI), V(ll), V(lll), V(IV), or V(V).

[0192]

[0129] In embodiments, the metal is Zn(ll), Fe(ll), Fe(lll), Mn(ll), Mn(lll), Mn(IV), Ni(ll), Ni(lll), Co(ll), Cu(l), Cu(ll), Sc(lll), Mo(ll), Mo(lll), or Mo(IV).

[0193]

[0130] In embodiments, the metal is Zn. In embodiments, the metal is Zn(ll).

[0194]

[0131] In embodiments, the metal is Fe. In embodiments, the metal is Fe(ll). In embodiments, the metal is Fe(lll).

[0195]

[0132] In embodiments, the metal is Mn. In embodiments, the metal is Mn(ll). In embodiments, the metal is Mn(lll). In embodiments, the metal is Mn(IV). In embodiments, the metal is Mn(V). In embodiments, the metal is Mn(VI).

[0196]

[0133] In embodiments, the metal is Ni. In embodiments, the metal is Ni(ll). In embodiments, the metal is Ni(lll).

[0197]

[0134] In embodiments, the metal is Ag. In embodiments, the metal is Ag(l).

[0198]

[0135] In embodiments, the metal is Co. In embodiments, the metal is Co(ll). In embodiments, the metal is Co(lll).

[0199]

[0136] In embodiments, the metal is Cu. In embodiments, the metal is Cu(l). In embodiments, the metal is Cu(ll). 2025-12-15

[0137] In embodiments, the metal is Au. In embodiments, the metal is Au(l). In embodiments, the metal is Au(lll).

[0200]

[0138] In embodiments, the metal is Pd. In embodiments, the metal is Pd(ll).

[0201]

[0139] In embodiments, the metal is Sc. In embodiments, the metal is Sc(lll).

[0202]

[0140] In embodiments, the metal is Mo. In embodiments, the metal is Mo(ll). In embodiments, the metal is Mo(lll). In embodiments, the metal is Mo(IV). In embodiments, the metal is Mo(V). In embodiments, the metal is Mo(VI).

[0203]

[0141] In embodiments, the metal is W. In embodiments, the metal is W(ll). In embodiments, the metal is W(lll). In embodiments, the metal is W(IV). In embodiments, the metal is W(V). In embodiments, the metal is W(VI).

[0204]

[0142] In embodiments, the metal is Cr. In embodiments, the metal is Cr(ll). In embodiments, the metal is Cr(lll). In embodiments, the metal is Cr(IV). In embodiments, the metal is Cr(V). In embodiments, the metal is Cr(VI).

[0205]

[0143] In embodiments, the metal is V. In embodiments, the metal is V(ll). In embodiments, the metal is V(lll). In embodiments, the metal is V(IV). In embodiments, the metal is V(V).

[0206]

[0144] In embodiments, the metal is a post-transition metal, lanthanide, or actinide. In embodiments, the metal is a post-transition metal. In embodiments, the metal is a lanthanide. In embodiments, the metal is an actinide.

[0207]

[0145] In embodiments, the metal is a metal ion. In embodiments, the metal ion is a Zn, Fe, Ag, Co, Cu, Ni, Mn, Au, Pd, Sc, Mo, W, Cr, or V ion.

[0208]

[0146] In embodiments, the metal is useful for diagnostic, imaging, or combined diagnostic-therapeutic applications. Therapeutic applications of complexes comprising certain antioxidant metals are described elsewhere herein. Additionally, metals useful for diagnostic, imaging, or combined diagnostic-therapeutic purposes include paramagnetic, superparamagnetic, radioactive, and luminescent metals, including gadolinium (Gd), europium (Eu), terbium (Tb), dysprosium (Dy), manganese (Mn), iron (Fe), copper (Cu), cobalt (Co), yttrium (Y), lutetium (Lu), actinium (Ac), thorium (Th), and isotopes thereof. For example, complexes comprising Gd may be useful tools for magnetic resonance imaging, and complexes comprising a luminescent metal may be useful for imaging, such as for measuring complex distribution or dissociation, or imaging body systems and tissues into which a complex partitions.

[0209] d. MDMA-Metal Complexes

[0210]

[0147] In embodiments, provided are metal-drug coordination complexes comprising a metal coordinated to one or more pharmacologically active agents having the structure of Formula (I), 2025-12-15

[0211]

[0212] wherein L is a ligand moiety or H; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

[0213]

[0148] In embodiments, a disclosed complex comprises one or more molecules of MDMA coordinated to a metal (which may be referred to in embodiments herein as an [MDMA][M] complex). In embodiments, the [MDMA][M] complex comprises one or more molecules of MDMA and one or more coordinating solvent molecules coordinated to a metal (M). In embodiments, the [MDMA][M] complex comprises one or more molecules of MDMA and one or more coordinating anions coordinated to a metal (M). In embodiments, the [MDMA][M] complex comprises one or more molecules of MDMA, one or more coordinating solvent molecules, and one or more coordinating anions coordinated to a metal.

[0214]

[0149] A “coordinating anion” refers to an anionic atom or anionic molecule that is capable of forming a coordination interaction with a metal, including through donation of one or more lone pairs to the metal, and that occupies one or more coordination sites of the metal (either transiently or persistently). Coordinating anions are known to those of skill in the art, and include, for example, halides (e.g., Cl“, Br, l“), pseudohalides (e.g., CN“, SCN“), oxoanions (e.g., N03“, N02“, SO42-, SO32-, CO32-, HCO3“, P043-, HPO42-, H2PO4“), carboxylates (e.g., acetate, formate, propionate, citrate), alkoxides, phenolates, and thiolates.

[0215]

[0150] A “coordinating solvent” or “coordinating solvent molecule” refers a solvent molecule that is capable of forming a coordination interaction with a metal, including through donation of one or more lone pairs to the metal, and that occupies one or more coordination sites of the metal (either transiently or persistently). Coordinating solvents may bind in a monodentate or multidentate manner and may reversibly associate with the metal. Exemplary coordinating solvents include water, alcohols, amides (e.g., N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone), sulfoxides (e.g., dimethyl sulfoxide), nitriles (e.g., acetonitrile), ethers, and heterocyclic bases (e.g., pyridine).

[0216]

[0151] In embodiments, the MDMA in a [MDMA][M] complex coordinates to the metal as a monodentate ligand. In embodiments, the MDMA in a [MDMA][M] complex coordinates to the metal as a bidentate ligand. In embodiments, the MDMA in a [MDMA][M] complex coordinates to the metal as a tridentate ligand.

[0217]

[0152] In embodiments, the [MDMA][M] complex is a four-coordinate complex. In embodiments, the four-coordinate [MDMA][M] complex has the structure of Formula (M4): 2025-12-15

[0218]

[0219] wherein M is a metal, RNis absent or H, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom (e.g., N or 0) from an additional molecule of MDMA.

[0220]

[0153] Exemplary four-coordinate [MDMA][M] complexes of Formula (M4) include Formulae (M4i) to (M4xiii):

[0221]

[0222] 2025-12-15

[0223]

[0224]

[0154] In embodiments, the four-coordinate [MDMA][M] complex has tetrahedral geometry. In embodiments, the four-coordinate complex has square planar geometry.

[0225]

[0155] In embodiments, the [MDMA][M] complex is a five-coordinate complex. In embodiments, the five-coordinate [MDMA][M] complex has the structure of Formula (M5):

[0226]

[0227] (M5),

[0228] wherein M is a metal, RNis absent or H, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA.

[0229]

[0156] In embodiments, the five-coordinate [MDMA][M] complex has square pyramidal geometry. In embodiments, the five-coordinate [MDMA][M] complex has trigonal bipyramidal geometry.

[0230]

[0157] In embodiments, the [MDMA][M] complex is a six-coordinate complex. In embodiments, the six-coordinate [MDMA][M] complex has the structure of Formula (M6):

[0231]

[0232] (M6),

[0233] wherein M is a metal, RNis absent or H, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA.

[0234]

[0158] In embodiments, the six-coordinate [MDMA][M] complex has octahedral geometry. In embodiments, the six-coordinate [MDMA][M] complex has trigonal prismatic geometry.

[0235]

[0159] In embodiments, a disclosed complex comprises one or more molecules of a MDMA-AA coordinated to a metal (which may be referred to in embodiments as an [MDMA-AA][M] complex). In 2025-12-15 embodiments, the [MDMA-AA][M] complex comprises one or more molecules of MDMA-AA and one or more coordinating solvent molecules coordinated to a metal. In embodiments, the [MDMA-AA][M] complex comprises one or more molecules of MDMA-AA and one or more coordinating anions coordinated to a metal. In embodiments, the [MDMA-AA][M] complex comprises one or more molecules of MDMA-AA, one or more coordinating solvent molecules, and one or more coordinating anions coordinated to a metal.

[0236]

[0160] In embodiments, the MDMA-AA in a [MDMA-AA][M] complex coordinates to the metal as a monodentate ligand. In embodiments, the MDMA-AA in a [MDMA-AA][M] complex coordinates to the metal as a bidentate ligand. In embodiments, the MDMA-AA in a [MDMA-AA][M] complex coordinates to the metal as a tridentate ligand. In embodiments, the MDMA-AA in a [MDMA-AA][M] complex coordinates to the metal as a tetradentate ligand.

[0237]

[0161] In embodiments, the [MDMA-AA][M] complex is a four-coordinate complex. In embodiments, the four-coordinate [MDMA-AA][M] complex has the structure of Formula (A4a):

[0238]

[0239] (A4a),

[0240] wherein M is a metal, RNis absent or H, R is an amino acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA.

[0241]

[0162] In embodiments, the four-coordinate [MDMA-AA][M] complex has the structure of Formula (A4b):

[0242]

[0243] (A4b),

[0244] wherein M is a metal, RNis absent or H, R is an amino acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA.

[0245]

[0163] In embodiments, the [MDMA-AA][M] complex is a five-coordinate complex. In embodiments, the five-coordinate [MDMA-AA][M] complex has the structure of Formula (A5a):

[0246] R I H

[0247] A, x

[0248] Nk iv

[0249] r Ox'Mv,'M \-X

[0250] xX

[0251]

[0252] 2025-12-15 wherein M is a metal, RNis absent or H, R is an amino acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA.

[0253]

[0164] In embodiments, the five-coordinate [MDMA-AA][M] complex has the structure of Formula (A5b):

[0254]

[0255] (A5b),

[0256] wherein M is a metal, RNis absent or H, R is an amino acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA.

[0257]

[0165] In embodiments, the [MDMA-AA][M] complex is a six-coordinate complex. In embodiments, the six-coordinate [MDMA-AA][M] complex has the structure of Formula (A6a):

[0258]

[0259] (A6a), wherein M is a metal, RNis absent or H, R is an amino acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA.

[0260]

[0166] In embodiments, the six-coordinate [MDMA-AA][M] complex has the structure of Formula (A6b):

[0261]

[0262] wherein M is a metal, RNis absent or H, R is an amino acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA.

[0263]

[0167] In embodiments, the MDMA-AA in a [MDMA-AA][M] complex coordinates to the metal as a bidentate ligand. In embodiments, both metal-binding moieties of a bidentate MDMA-AA are from the amino acid moiety. Exemplary such [MDMA-AA][M] complexes include: 2025-12-15

[0264]

[0265]

[0168] In embodiments, the amino acid side chain (shown as R in the foregoing Formulae) coordinates to the metal. Exemplary amino acids with coordinating side chains are described in the Ligand Moieties section above. For purposes of illustration, the Formulae below show exemplary binding modes for a four-coordinate MDMA-AA comprising cysteine (i.e., wherein R = — CH2SH), wherein M is a metal, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an

[0266]

[0267]

[0268] 2025-12-15

[0269]

[0270]

[0169] In embodiments wherein an active agent comprises a cysteine or cysteine analog moiety, resulting complexes may exhibit a binding mode described in Yoshinari et al. Coord Chem Rev. 2023;474: 214857.

[0271]

[0170] As would be readily appreciated by one of skill, other suitable amino acids may be substituted for cysteine. For example, a [MDMA-AA] comprising aspartic acid (R = — CH2COO), the carboxylate group may coordinate to the metal (as a monodendate or bidentate ligand) in a structure similar to those shown above. Likewise, similar binding modes may exist in five- and six-coordinate [MDMA-AA][M] complexes.

[0272]

[0171] In embodiments, the [MDMA-AA][M] complex is a four-coordinate chelate having the

[0273]

[0274]

[0275] R; wherein M is a metal, each R is an amino acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA. 2025-12-15

[0172] In embodiments, the [MDMA-AA][M] complex is a five-coordinate chelate having the

[0276]

[0277]

[0278] ; wherein M is a metal, each R is an amino acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA.

[0279]

[0173] In embodiments, the [MDMA-AA][M] complex is a six-coordinate chelate having the

[0280]

[0281] structure of 2025-12-15

[0282]

[0283] acid side chain, and each X is independently a coordinating solvent, a coordinating anion, or a coordinating atom from an additional molecule of MDMA-AA.

[0284]

[0174] In embodiments, wherein the [MDMA-AA] comprises an amino acid with a coordinating side chain, the [MDMA-AA] may coordinate to the ligand as a tridentate ligand, with the amino acid side chain coordinating to the metal (as shown in the exemplary tridentate complexes above).

[0285]

[0175] In embodiments, the complex has the structure of: 2025-12-15

[0286]

[0287] wherein M is a metal, each R is an amino acid side chain. In embodiments, R is H, C1-C12alkyl, C1-C6hydroxyalkyl, C1-C6alkylthio, C1-C6thioalkyl, C1-C6aminoalkyl, C1-C6carboxyalkyl, C1-C6alkylene-C6-C12aryl, C1-C6alkylene— (3- to 10-membered heteroaryl), C1-C6alkylene— guanidino, C1-C6alkylene-CONH2; each of which may be optionally substituted. In embodiments, R is H. In embodiments, R is C1-C12alkyl. In embodiments, R is C1-C6alkyl. In embodiments, R is methyl. In embodiments, R is ethyl. In embodiments, R is propyl. In embodiments, R is n-propyl. In embodiments, R is isopropyl. In embodiments, R is butyl. In embodiments, R is sec-butyl. In embodiments, R is isobutyl. In embodiments, R is tert-butyl. In embodiments, R is C1-C6hydroxyalkyl. In embodiments, R is -CH2OH (i.e., hydroxymethyl). In embodiments, R is C2hydroxyalkyl (i.e., a hydroxyethyl). In embodiments, R is -CH2-CH2OH. In embodiments, R is -C(OH)H-CH3. In embodiments, R is C1-C6alkylthio. In embodiments, R is C1-C6thioalkyl. In embodiments, R is -CH2SH. In embodiments, R is -CH2-CH2-SCH3. In embodiments, R is C1-C6aminoalkyl. In embodiments, R is -(CH2)4-NH2or -(CH2)4-NH3+. In embodiments, R is C1-C6carboxyalkyl. In embodiments, R is C1-C6alkylene-COO’. In embodiments, R is -CH2-COO’. In embodiments, R is -(CH2)2-COO’. In embodiments, R is C1-C6alkylene-COOH. In embodiments, R is -CH2-COOH. In embodiments, R is -(CH2)2-COOH. In embodiments, R is C1-C6alkylene-C6-C12aryl. In embodiments, R is C1-C6alkylene— phenyl. In embodiments, R is -CH2-phenyl. In embodiments, R is -CH2-(4-hydroxyphenyl). In embodiments, R is C1-C6alkylene— (3- to 10-membered heteroaryl). In embodiments, R is C1-C6alkylene— indolyl. In embodiments, R is — CH2— indolyl. In embodiments, R is — CH2— (3-indolyl). In embodiments, R is C1-C6alkylene— imidazolyl. In embodiments, R is —CH2— imidazolyl. In embodiments, R is — CH2— (imidazol-4-yl). In embodiments, R is C1-C6alkylene— guanidino. In embodiments, R is —(CH2)3— guanidino. In embodiments, R is C1-C6alkylene-CONH2. In embodiments, R is -CH2-CONH2. In embodiments, R is -(CH2)2-CONH2.

[0288]

[0176] In embodiments, the complex is selected from Table 1, wherein the metal may further comprise one or more additional coordinating ligands as previously described, including coordinating solvent molecules, coordinating anions, or any combination thereof. 2025-12-15

[0289] Table 2. Exemplary Metal-Drug Complexes

[0290]

[0291] 2025-12-15

[0292]

[0293] 2025-12-15

[0294]

[0295] 2025-12-15

[0296]

[0297]

[0177] In embodiments, the complex of Table 1 further comprises one or more additional coordinating ligands, such as one or more coordinating solvent molecules and / or anions. In embodiments, the complex further comprises one coordinating solvent molecule and / or anion. In embodiments, the complex further comprises one coordinating solvent molecule. In embodiments, the complex further comprises one coordinating anion. In embodiments, the complex further comprises two coordinating solvent molecules and / or anions. In embodiments, the complex further comprises two coordinating solvent molecules. In embodiments, the complex further comprises two H2O molecules coordinated to the metal. In embodiments, the complex further comprises two coordinating anions.

[0298]

[0178] In embodiments, a complex of Table 1 comprises a metal (M) selected from the group consisting of Zn, Fe, Mn, Ni, Ag, Co, Cu, Au, Pd, Sc, Mo, W, Cr, and V. In embodiments, M is Zn(ll), Fe(ll), Fe(lll), Mn(ll), Mn(lll), Mn(IV), Mn(V), Mn(VI), Ni(ll), Ni(lll), Ag(l), Co(ll), Co(lll), Cu(l), Cu(ll), Au(l), Au(lll), Pd(ll), Sc(lll), Mo(ll), Mo(lll), Mo(IV), Mo(V), Mo(VI), W(ll), W(lll), W(IV), W(V), W(VI), Cr(ll), Cr(lll), Cr(IV), Cr(V), Cr(VI), V(ll), V(lll), V(IV), or V(V). In some embodiments, M is Zn(ll). In some embodiments, M is Fe(ll). In some embodiments, M is Fe(lll). In some embodiments, M is Mn(ll). In some embodiments, M is Mn(lll). In some embodiments, M is Mn(IV). In some embodiments, M is Mn(V). In some embodiments, M is Mn(VI). In some embodiments, M is Ni(ll). In some embodiments, M is Ni(lll). In some embodiments, M is Ag(l). In some embodiments, M is Co(ll). In some embodiments, M is Co(lll). In some embodiments, M is Cu(l). In some embodiments, M is Cu(ll). In some embodiments, M is Au(l). In some embodiments, M is Au(lll). In some embodiments, M is Pd(ll). In some embodiments, M is Sc(lll). In some embodiments, M is Mo(ll). In some embodiments, M is Mo(lll). In some embodiments, M is Mo(IV). In some embodiments, M is Mo(V). In some embodiments, M is Mo(VI). In some embodiments, M is W(ll). In some embodiments, M is W(lll). In some embodiments, M is W(IV). In some embodiments, M is W(V). In some embodiments, M is W(VI). In some embodiments, M is Cr(ll). In some embodiments, M is Cr(lll). In some embodiments, M is Cr(IV). In some embodiments, M is Cr(V). In some embodiments, M is Cr(VI). In some embodiments, M is V(ll). In some embodiments, M is V(lll). In some embodiments, M is V(IV). In some embodiments, M is V(V).

[0299]

[0179] In embodiments, a complex of Table 1 has square planar geometry. In embodiments, a complex of Table 1 has tetrahedral geometry. 2025-12-15

[0180] In embodiments, a complex of Table 1 has square pyramidal or trigonal bipyramidal geometry, such as in embodiments wherein the complex further comprises one additional coordinating solvent molecule or anion, or wherein one additional coordinating atom of a MDMA-AA is coordinated to the metal.

[0300]

[0181] In embodiments, a complex of Table 1 has octahedral geometry, such as in embodiments wherein the complex further comprises two additional coordinating solvent molecules and / or anions, or wherein the complex or wherein two additional coordinating atoms of a MDMA-AA are coordinated to the metal.

[0301]

[0182] In embodiments, the complex has the structure of:

[0302]

[0303] wherein M is a metal, each R is an amino acid side chain, and each X is independently absent, a coordinating solvent, or a coordinating anion. In embodiments, one X is absent. In embodiments, both of X are absent. In embodiments, one X is a coordinating solvent molecule and the other X is absent. In embodiments, one X is a coordinating solvent molecule and the other X is a coordinating anion. In embodiments, both of X are coordinating solvent molecules. In embodiments, both of X are coordinating anions. In embodiments, R is H, C1-C12alkyl, C1-C6hydroxyalkyl, C1-C6alkylthio, C1-C6thioalkyl, C1-C6aminoalkyl, C1-C6carboxyalkyl, C1-C6alkylene-C6-C12aryl, C1-C6alkylene— (3- to 10-membered heteroaryl), C1-C6alkylene— guanidino, C1-C6alkylene-CONH2; each of which may be optionally substituted. In embodiments, R is H. In embodiments, R is C1-C12alkyl. In embodiments, R is C1-C6alkyl. In embodiments, R is methyl. In embodiments, R is ethyl. In embodiments, R is propyl. In embodiments, R is n-propyl. In embodiments, R is isopropyl. In embodiments, R is butyl. In embodiments, R is sec-butyl. In embodiments, R is isobutyl. In embodiments, R is tert-butyl. In embodiments, R is C1-C6hydroxyalkyl. In embodiments, R is -CH2OH (i.e., hydroxymethyl). In embodiments, R is C2hydroxyalkyl (i.e., a hydroxyethyl). In embodiments, R is -CH2-CH2OH. In embodiments, R is -C(OH)H-CH3. In embodiments, R is C1-C6alkylthio. In embodiments, R is C1-C6thioalkyl. In embodiments, R is -CH2SH. In embodiments, R is -CH2-CH2-SCH3. In embodiments, R is C1-C6aminoalkyl. In embodiments, R is –(CH2)4–NH2or -(CH2)4-NH3+. In embodiments, R is C1-C6carboxyalkyl. In embodiments, R is C1-C6alkylene-COO’. In embodiments, R is -CH2-COO’. In embodiments, R is -(CH2)2-COO_. In embodiments, R is C1-C6alkylene-COOH. In embodiments, R is -CH2-COOH. In embodiments, R is -(CH2)2-COOH. In embodiments, R is C1-C6alkylene-C6-C12aryl. In embodiments, R is C1-C6alkylene— phenyl. In 2025-12-15 embodiments, R is -CH2-phenyl. In embodiments, R is -CH2-(4-hydroxyphenyl). In embodiments, R is C1-C6alkylene— (3- to 10-membered heteroaryl). In embodiments, R is C1-C6alkylene— indolyl. In embodiments, R is —CH2— indolyl. In embodiments, R is — CH2— (3-indolyl). In embodiments, R is C1-C6alkylene— imidazolyl. In embodiments, R is —CH2— imidazolyl. In embodiments, R is — CH2— (imidazol-4-yl). In embodiments, R is C1-C6alkylene— guanidino. In embodiments, R is — (CH2)3— guanidino. In embodiments, R is C1-C6alkylene-CONH2. In embodiments, R is -CH2-CONH2. In embodiments, R is -(CH2)2-CONH2.

[0304]

[0183] Exemplary octahedral complexes are provided in Table 2.

[0305] IR

[0306] / x yk,,

[0307] / Ii T I Y F2

[0308] X JI I 0 / X

[0309] x / iY i ll >

[0310] R 1

[0311] M R X

[0312] Zn(ll) — H H2O

[0313] Fe(ll) — H H2O

[0314] Fe(lll) — H H2O

[0315] Mn(ll) — H H2O

[0316] Mn(lll) — H H2O

[0317] Ni(ll) — H H2O

[0318] Co(ll) — H H2O

[0319] Cu(ll) — H H2O

[0320] Sc(lll) — H H2O

[0321] Mo(lll) — H H2O

[0322] Mo(IV) — H H2O

[0323] Zn(ll) -CH3H2O

[0324] Fe(ll) -CH3H2O

[0325] Fe(lll) -CH3H2O

[0326] Mn(ll) -CH3H2O

[0327] Mn(lll) -CH3H2O

[0328] Ni(ll) -CH3H2O

[0329] Co(ll) -CH3H2O

[0330] Cu(ll) -CH3H2O

[0331] Sc(lll) -CH3H2O

[0332] Mo(lll) -CH3H2O

[0333] Mo(IV)

[0334]

[0335] -CH3H2O 2025-12-15

[0336] Zn(ll) -CH2-CH(CH3)2H2O Fe(ll) -CH2-CH(CH3)2H2O Fe(lll) -CH2-CH(CH3)2H2O Mn(ll) -CH2-CH(CH3)2H2O Mn(lll) -CH2-CH(CH3)2H2O Ni(ll) -CH2-CH(CH3)2H2O Co(ll) -CH2-CH(CH3)2H2O Cu(ll) -CH2-CH(CH3)2H2O Sc(lll) -CH2-CH(CH3)2H2O Mo(lll) -CH2-CH(CH3)2H2O Mo(IV) -CH2-CH(CH3)2H2O Zn(ll) -CH(CH3)-CH2CH3H2O Fe(ll) -CH(CH3)-CH2CH3H2O Fe(lll) -CH(CH3)-CH2CH3H2O Mn(ll) -CH(CH3)-CH2CH3H2O Mn(lll) -CH(CH3)-CH2CH3H2O Ni(ll) -CH(CH3)-CH2CH3H2O Co(ll) -CH(CH3)-CH2CH3H2O Cu(ll) -CH(CH3)-CH2CH3H2O Sc(lll) -CH(CH3)-CH2CH3H2O Mo(lll) -CH(CH3)-CH2CH3H2O Mo(IV) -CH(CH3)-CH2CH3H2O Zn(ll) -CH(CH3)2H2O Fe(ll) -CH(CH3)2H2O Fe(lll) -CH(CH3)2H2O Mn(ll) -CH(CH3)2H2O Mn(lll) -CH(CH3)2H2O Ni(ll) -CH(CH3)2H2O Co(ll) -CH(CH3)2H2O Cu(ll) -CH(CH3)2H2O Sc(lll) -CH(CH3)2H2O Mo(lll) -CH(CH3)2H2O Mo(IV) -CH(CH3)2H2O Zn(ll) — CH2Ph H2O Fe(ll) — CH2Ph H2O Fe(lll) — CH2Ph H2O

[0337]

[0338] Mn(ll) — CH2Ph H2O 2025-12-15

[0339] Mn(lll) — CH2Ph H2O Ni(ll) — CH2Ph H2O Co(ll) — CH2Ph H2O Cu(ll) — CH2Ph H2O Sc(lll) — CH2Ph H2O Mo(lll) — CH2Ph H2O Mo(IV) — CH2Ph H2O Zn(ll) -CH2OH H2O Fe(ll) -CH2OH H2O Fe(lll) -CH2OH H2O Mn(ll) -CH2OH H2O Mn(lll) -CH2OH H2O Ni(ll) -CH2OH H2O Co(ll) -CH2OH H2O Cu(ll) -CH2OH H2O Sc(lll) -CH2OH H2O Mo(lll) -CH2OH H2O Mo(IV) -CH2OH H2O Zn(ll) — CH2-(3-indolyl) H2O Fe(ll) — CH2-(3-indolyl) H2O Fe(lll) — CH2-(3-indolyl) H2O Mn(ll) — CH2-(3-indolyl) H2O Mn(lll) — CH2-(3-indolyl) H2O Ni(ll) — CH2-(3-indolyl) H2O Co(ll) — CH2-(3-indolyl) H2O Cu(ll) — CH2-(3-indolyl) H2O Sc(lll) — CH2-(3-indolyl) H2O Mo(lll) — CH2-(3-indolyl) H2O Mo(IV) — CH2-(3-indolyl) H2O Zn(ll) -(CH2)4-NH3+H2O Fe(ll) -(CH2)4-NH3+H2O Fe(lll) -(CH2)4-NH3+H2O Mn(ll) -(CH2)4-NH3+H2O Mn(lll) -(CH2)4-NH3+H2O Ni(ll) -(CH2)4-NH3+H2O Co(ll) -(CH2)4-NH3+H2O

[0340]

[0341] Cu(ll) -(CH2)4-NH3+H2O 2025-12-15

[0342] Sc(lll) -(CH2)4-NH3+H2O Mo(lll) -(CH2)4-NH3+H2O Mo(IV) -(CH2)4-NH3+H2O Zn(ll) -(CH2)2-COO-H2O Fe(ll) -(CH^-CH, H2O Fe(lll) -(CH^-CH, H2O Mn(ll) -(CH^-CH, H2O Mn(lll) -(CH^-CH, H2O Ni(ll) -(CH^-CH, H2O Co(ll) -(CH^-CH, H2O Cu(ll) -(CH^-CH, H2O Sc(lll) -(CH^-CH, H2O Mo(lll) -(CH^-CH, H2O Mo(IV) -(CH^-CH,

[0343]

[0344] H2O

[0184] Additional exemplary complexes having octahedral geometry include:

[0345]

[0346] 2025-12-15

[0347]

[0348] and stereoisomers thereof.

[0349]

[0185] In embodiments, a complex comprises [Zn"(MDMA-Val)2], [Fe"(MDMA-Val)2], [Fe'"(MDMA-Val)2], [Mn"(MDMA-Val)2], [Mnl"(MDMA-Val)2], [Mnlv(MDMA-Val)2], [Ni"(MDMA-Val)2], [Nil"(MDMA-Val)2], [Co"(MDMA-Val)2], [Cu'(MDMA-Val)2], [Cu"(MDMA-Val)2], [Scl"(MDMA-Val)2], [Mo"(MDMA-Val)2], [Mol"(MDMA-Val)2], [Molv(MDMA-Val)2], [Zn"(MDMA-Gly)2], [Fe"(MDMA-Gly)2], [Fel"(MDMA-Gly)2], [Mn"(MDMA-Gly)2], [Mnl"(MDMA-Gly)2], [Mnlv(MDMA-Gly)2], [Ni"(MDMA-Gly)2], [Ni'"(MDMA-Gly)2], [Co"(MDMA-Gly)2], [Cu'(MDMA-Gly)2], [Cu"(MDMA-Gly)2], [Scl"(MDMA-Gly)2], [Mo"(MDMA-Gly)2], [Mo'"(MDMA-Gly)2], [Molv(MDMA-Gly)2], [Zn"(MDMA-Ala)2], [Fe"(MDMA-Ala)2], [Fe'"(MDMA-Ala)2], [Mn"(MDMA-Ala)2], [Mnl"(MDMA-Ala)2], [Mnlv(MDMA-Ala)2], [Ni"(MDMA-Ala)2], [Nil"(MDMA-Ala)2], [Co"(MDMA-Ala)2], [Cu'(MDMA-Ala)2], [Cu"(MDMA-Ala)2], [Scl"(MDMA-Ala)2], [Mo"(MDMA-Ala)2], [Mo'"(MDMA-Ala)2], [Molv(MDMA-Ala)2], [Zn"(MDMA-Leu)2], [Fe"(MDMA-Leu)2], [Fe'"(MDMA-Leu)2], [Mn"(MDMA-Leu)2], [Mnl"(MDMA-Leu)2], [Mnlv(MDMA-Leu)2], [Ni"(MDMA-Leu)2], [Ni'"(MDMA-Leu)2], [Co"(MDMA-Leu)2], [Cu'(MDMA-Leu)2], [Cu"(MDMA-Leu)2], [Sc'"(MDMA-Leu)2], [Mo"(MDMA-Leu)2], [Mo'"(MDMA-Leu)2], [Molv(MDMA-Leu)2], [Zn"(MDMA-lle)2], [Fe"(MDMA-lle)2], [Fe"l(MDMA-lle)2], [Mn"(MDMA-lle)2], [Mn"l(MDMA-lle)2], [Mnlv(MDMA-lle)2], [Ni"(MDMA-lle)2], [Ni'"(MDMA-lle)2], [Co"(MDMA-lle)2], [Cu'(MDMA-lle)2], [Cu"(MDMA-lle)2], [Sc"l(MDMA-lle)2], [Mo"(MDMA-lle)2], [Mo"l(MDMA-lle)2], [Molv(MDMA-lle)2], [Zn"(MDMA-Ser)2], [Fe"(MDMA-Ser)2], [Fe'"(MDMA-Ser)2], [Mn"(MDMA-Ser)2], [Mn'"(MDMA-Ser)2], [Mnlv(MDMA-Ser)2], [Ni"(MDMA-Ser)2], [Nil"(MDMA-Ser)2], [Co"(MDMA-Ser)2], [Cu'(MDMA-Ser)2], [Cu"(MDMA-Ser)2], [Sc'"(MDMA-Ser)2], [Mo"(MDMA-Ser)2], [Mo'"(MDMA-Ser)2], [Molv(MDMA-Ser)2], [Zn"(MDMA-Asn)2], [Fe"(MDMA-Asn)2], [Fe'"(MDMA-Asn)2], [Mn"(MDMA-Asn)2], [Mn'"(MDMA-Asn)2], [Mnlv(MDMA-Asn)2], [Ni"(MDMA-Asn)2], 2025-12-15 [Nil"(MDMA-Asn)2], [Co"(MDMA-Asn)2], [Cu'(MDMA-Asn)2], [Cu"(MDMA-Asn)2], [Scl"(MDMA-Asn)2], [Mo"(MDMA-Asn)2], [Mol"(MDMA-Asn)2], [Molv(MDMA-Asn)2], [Zn"(MDMA-Gln)2], [Fe"(MDMA-Gln)2], [Fel"(MDMA-Gln)2], [Mn"(MDMA-Gln)2], [Mnl"(MDMA-Gln)2], [Mnlv(MDMA-Gln)2], [Ni"(MDMA-Gln)2], [Ni'"(MDMA-Gln)2], [Co"(MDMA-Gln)2], [Cu'(MDMA-Gln)2], [Cu"(MDMA-Gln)2], [Scl"(MDMA-Gln)2], [Mo"(MDMA-Gln)2], [Mo'"(MDMA-Gln)2], [Molv(MDMA-Gln)2], [Zn"(MDMA-Phe)2], [Fe"(MDMA-Phe)2], [Fe'"(MDMA-Phe)2], [Mn"(MDMA-Phe)2], [Mnl"(MDMA-Phe)2], [Mnlv(MDMA-Phe)2], [Ni"(MDMA-Phe)2], [Ni'"(MDMA-Phe)2], [Co"(MDMA-Phe)2], [Cu'(MDMA-Phe)2], [Cu"(MDMA-Phe)2], [Scl"(MDMA-Phe)2], [Mo"(MDMA-Phe)2], [Mo'"(MDMA-Phe)2], [Molv(MDMA-Phe)2], [Zn"(MDMA-Tyr)2], [Fe"(MDMA-Tyr)2], [Fe'"(MDMA-Tyr)2], [Mn"(MDMA-Tyr)2], [Mnl"(MDMA-Tyr)2], [Mnlv(MDMA-Tyr)2], [Ni"(MDMA-Tyr)2], [Ni'"(MDMA-Tyr)2], [Co"(MDMA-Tyr)2], [Cu'(MDMA-Tyr)2], [Cu"(MDMA-Tyr)2], [Sc'"(MDMA-Tyr)2], [Mo"(MDMA-Tyr)2], [Mo'"(MDMA-Tyr)2], [Molv(MDMA-Tyr)2], [Zn"(MDMA-Trp)2], [Fe"(MDMA-Trp)2], [Fel"(MDMA-Trp)2], [Mn"(MDMA-Trp)2], [Mnl"(MDMA-Trp)2], [Mnlv(MDMA-Trp)2], [Ni"(MDMA-Trp)2], [Nil"(MDMA-Trp)2], [Co"(MDMA-Trp)2], [Cu'(MDMA-Trp)2], [Cu"(MDMA-Trp)2], [Sc'"(MDMA-Trp)2], [Mo"(MDMA-Trp)2], [Mo'"(MDMA-Trp)2], [Molv(MDMA-Trp)2], [Zn"(MDMA-Cys)2], [Fe"(MDMA-Cys)2], [Fe'"(MDMA-Cys)2], [Mn"(MDMA-Cys)2], [Mnl"(MDMA-Cys)2], [Mnlv(MDMA-Cys)2], [Ni"(MDMA-Cys)2], [Nil"(MDMA-Cys)2], [Co"(MDMA-Cys)2], [Cu'(MDMA-Cys)2], [Cu"(MDMA-Cys)2], [Scl"(MDMA-Cys)2], [Mo"(MDMA-Cys)2], [Mo"'(MDMA-Cys)2], [Molv(MDMA-Cys)2], [Zn"(MDMA-NAC)2], [Fe"(MDMA-NAC)2], [Fe'"(MDMA-NAC)2], [Mn"(MDMA-NAC)2], [Mn'"(MDMA-NAC)2], [Mnlv(MDMA-NAC)2], [Ni"(MDMA-NAC)2], [Ni'"(MDMA-NAC)2], [Co"(MDMA-NAC)2], [Cu'(MDMA-NAC)2], [Cu"(MDMA-NAC)2], [Sc"'(MDMA-NAC)2], [MO"(MDMA-NAC)2], [MO'"(MDMA-NAC)2], [MOIV(MDMA-NAC)2], [Zn"(MDMA-Met)2], [Fe"(MDMA-Met)2], [Fe'"(MDMA-Met)2], [Mn"(MDMA-Met)2], [Mnl"(MDMA-Met)2], [Mnlv(MDMA-Met)2], [Ni"(MDMA-Met)2], [Nil"(MDMA-Met)2], [Co"(MDMA-Met)2], [Cu'(MDMA-Met)2], [Cu"(MDMA-Met)2], [Sc'"(MDMA-Met)2], [Mo"(MDMA-Met)2], [Mo'"(MDMA-Met)2], [Molv(MDMA-Met)2], [Zn"(MDMA-Sec)2], [Fe"(MDMA-Sec)2], [Fe'"(MDMA-Sec)2], [Mn"(MDMA-Sec)2], [Mnl"(MDMA-Sec)2], [Mnlv(MDMA-Sec)2], [Ni"(MDMA-Sec)2], [Nil"(MDMA-Sec)2], [Co"(MDMA-Sec)2], [Cu'(MDMA-Sec)2], [Cu"(MDMA-Sec)2], [Scl"(MDMA-Sec)2], [Mo"(MDMA-Sec)2], [Mo'"(MDMA-Sec)2], [Molv(MDMA-Sec)2], [Zn"(MDMA-Arg)2], [Fe"(MDMA-Arg)2], [Fe'"(MDMA-Arg)2], [Mn"(MDMA-Arg)2], [Mnl"(MDMA-Arg)2], [Mnlv(MDMA-Arg)2], [Ni"(MDMA-Arg)2], [Ni'"(MDMA-Arg)2], [Co"(MDMA-Arg)2], [Cu'(MDMA-Arg)2], [Cu"(MDMA-Arg)2], [Scl"(MDMA-Arg)2], [Mo"(MDMA-Arg)2], [Mo'"(MDMA-Arg)2], [Molv(MDMA-Arg)2], [Zn"(MDMA-His)2], [Fe"(MDMA-His)2], [Fel"(MDMA-His)2], [Mn"(MDMA-His)2], [Mn'"(MDMA-His)2], [Mnlv(MDMA-His)2], [Ni"(MDMA-His)2], 2025-12-15 [Ni"l(MDMA-His)2], [Co"(MDMA-His)2], [Cu'(MDMA-His)2], [Cu"(MDMA-His)2], [Scl"(MDMA-His)2], [Mo"(MDMA-His)2], [Mo"'(MDMA-His)2], [Molv(MDMA-His)2], [Zn"(MDMA-Lys)2], [Fe"(MDMA-Lys)2], [Felll(MDMA-Lys)2], [Mn"(MDMA-Lys)2], [Mn'"(MDMA-Lys)2], [Mnlv(MDMA-Lys)2], [Ni"(MDMA-Lys)2], [Nil"(MDMA-Lys)2], [Co"(MDMA-Lys)2], [Cu'(MDMA-Lys)2], [Cu"(MDMA-Lys)2], [Sc"l(MDMA-Lys)2], [Mo"(MDMA-Lys)2], [Molll(MDMA-Lys)2], [Molv(MDMA-Lys)2], [Zn"(MDMA-Asp)2], [Fe"(MDMA-Asp)2], [FeIH(MDMA-Asp)2], [Mn"(MDMA-Asp)2], [Mnl"(MDMA-Asp)2], [Mnlv(MDMA-Asp)2], [Ni"(MDMA-Asp)2], [Nil"(MDMA-Asp)2], [Co"(MDMA-Asp)2], [Cu'(MDMA-Asp)2], [Cu"(MDMA-Asp)2], [Scl"(MDMA-Asp)2], [Mo"(MDMA-Asp)2], [Mo"l(MDMA-Asp)2], [Molv(MDMA-Asp)2], [Zn"(MDMA-Glu)2], [Fe"(MDMA-Glu)2], [Fel"(MDMA-Glu)2], [Mn"(MDMA-Glu)2], [Mn'"(MDMA-Glu)2], [Mnlv(MDMA-Glu)2], [Ni"(MDMA-Glu)2], [NiHI(MDMA-Glu)2], [Co"(MDMA-Glu)2], [Cu'(MDMA-Glu)2], [Cu"(MDMA-Glu)2], [Scl"(MDMA-Glu)2], [Mo"(MDMA-Glu)2], [MO'"(MDMA-GIU)2], [MOIV(MDMA-GIU)2], [Zn"(MDMA-Pro)2], [Fe"(MDMA-Pro)2], [FeIH(MDMA-Pro)2], [Mn"(MDMA-Pro)2], [Mnl"(MDMA-Pro)2], [Mnlv(MDMA-Pro)2], [Ni"(MDMA-Pro)2], [Nil"(MDMA-Pro)2], [Co"(MDMA-Pro)2], [Cu'(MDMA-Pro)2], [Cu"(MDMA-Pro)2], [Scl"(MDMA-Pro)2], [Mo"(MDMA-Pro)2], [MoIH(MDMA-Pro)2], or [Molv(MDMA-Pro)2]; and zero, one, or two additional solvent molecules, anions, or additional coordinating ligands.

[0350]

[0186] As previously described, a complex may further comprise one or more additional coordinating ligands, such as one or more coordinating solvent molecules and / or anions. In embodiments, a complex further comprises one or more coordinating ligands selected to provide a desired property (e.g., a physical, chemical, or biological property) to the complex. Administration of such mixed-ligand complexes comprising one or more additional ligands coordinated to the metal, but not conjugated to the active agent, may provide a beneficial or desired effect, such as a synergistic effect.

[0351]

[0187] In embodiments, a complex comprises one or more additional coordinating ligands that provide an antioxidant effect. Exemplary antioxidant ligands include N-acetylcysteine (NAC), cysteine, glutathione, ascorbate, dehydroascorbate, a-lipoate, dihydrolipoate, tocopherols, urate, and polyphenols (e.g., catechols, gallates). Administration of complexes comprising one or more additional antioxidant ligands may deliver the antioxidant ligands to tissues into which the complex partitions and / or an active agent produces a pharmacological effect.

[0352]

[0188] In embodiments, a complex comprises one or more additional coordinating ligands that modify the bulk or molecular properties of the complex, including size, shape, coordination number, charge, dipole moment, polarizability, lipophilicity (e.g., logP), hydrophilicity, solubility, crystallinity, and stability. In general, suitable ligands for coordinating a selected metal are known to those of skill in the art, and 2025-12-15 include, for example, monodentate, bidentate, tridentate, tetradentate, and polydentate ligands; neutral, anionic, and cationic ligands; and σ-donating, π-donating, and / or π-accepting ligands.

[0353]

[0189] In embodiments, a complex comprises one or more additional coordinating ligands that modify the pharmacokinetic (e.g., absorption, distribution, metabolism, excretion, enzyme targeting) properties of the complex. In embodiments, a ligand is selected to alter the rate of metal-ligand dissociation, rate of dissociation of the active agent(s) from the metal, membrane permeability, plasma protein binding, tissue partitioning, or clearance rate. In one example, a complex comprising an active agent and an additional coordinating ligand that is sterically bulky may slow the metabolism of the complex. In another example, a complex comprising an active agent and an additional coordinating ligand that is lipophilic may increase the membrane permeability and CNS penetration of the complex.

[0354]

[0190] The disclosure will be understood to also encompass pharmaceutically acceptable salts of disclosed complexes. The term “pharmaceutically acceptable salt” refers to a salt prepared from pharmaceutically acceptable non-toxic acids, bases, and salts, and which may be synthesized by conventional chemical methods. For therapeutic use, salts of the complexes are those wherein the counter-ion is pharmaceutically acceptable. One of ordinary skill in the art can select from among a wide variety of available counterions those that are pharmaceutically acceptable. In specific applications, the selection of a given anion or cation for preparation of a salt may modify physicochemical properties such as solubility, crystallinity, hygroscopicity, stability, and formulation compatibility.

[0355]

[0191] In embodiments, formation of a disclosed complex from a metal salt precursor comprising a cationic metal and one or more anionic counterions results in a positively charged coordination complex that is associated with the same one or more anionic counterions. For example, in embodiments wherein a complex is produced from the reaction between the metal salt precursor [Zn(H2O)6](NO3)2and an active agent, the resulting complex may be associated with one or more nitrate (NO3-) anions. In another example, in embodiments wherein a complex is produced from the reaction between the metal salt precursor [Fe(H2O)6]Cl3and an active agent, the resulting complex may be associated with one or more chloride (Cl-) anions. Salts of complexes can also be formed by exchanging one or more counterions associated with a complex for a different counterion, such as by ion-exchange, metathesis, precipitation, dialysis, chromatography, or treatment with a salt comprising the desired counterion, as will be understood by those of skill in the art. Exemplary anionic counterions suitable for association with disclosed complexes include halides (e.g., chloride, bromide, iodide), inorganic oxyanions (e.g., nitrate, nitrite, sulfate, bisulfate, phosphate, hydrogen phosphate, carbonate, bicarbonate, perchlorate), organic carboxylates (e.g., acetate, propionate, butyrate, lactate, malate, tartrate, citrate, succinate, fumarate, oxalate, gluconate, ascorbate), sulfonates (e.g., methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, naphthalenesulfonate), and combinations thereof. 2025-12-15

[0192] Certain complexes may contain one or more ionizable groups (groups from which a proton can be removed (e.g., -COOH) or added (e.g., amines) or which can be quaternized (e.g., amines)), wherein one or more active agents of a complex comprise such ionizable groups. All possible ionic forms of such molecules and salts thereof are included in the present disclosure. Hence, also provided are acid and base addition salts of complexes wherein one or more active agents are ionized and associated with one or more counterions. Generally, such salts are prepared by reacting the free acid or base forms of these agents with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two. Exemplary salts include 2-hydroxyethanesulfonate, 2-naphthalenesulfonate, 2-napsylate, 3-hydroxy-2-naphthoate, 3-phenylpropionate, 4-acetamidobenzoate, acefyllinate, acetate, aceturate, adipate, alginate, aminosalicylate, ammonium, amsonate, ascorbate, aspartate, benzenesulfonate, benzoate, besylate, bicarbonate, bisulfate, bitartrate, borate, butyrate, calcium edetate, calcium, camphocarbonate, camphorate, camphorsulfonate, camsylate, carbonate, cholate, citrate, clavulariate, cyclopentanepropionate, cypionate, d-aspartate, d-camsylate, d-lactate, decanoate, dichloroacetate, digluconate, dodecylsulfate, edentate, edetate, edisylate, estolate, esylate, ethanesulfonate, ethyl sulfate, fumarate, furate, fusidate, galactarate (mucate), galacturonate, gallate, gentisate, gluceptate, glucoheptanoate, gluconate, glucuronate, glutamate, glutarate, glycerophosphate, glycolate, glycollylarsanilate, hemisulfate, heptanoate (enanthate), heptanoate, hexafluorophosphate, hexanoate, hexylresorcinate, hippurate, hybenzate, hydrabamine, hydrobromide, hydrobromide / bromide, hydrochloride, hydroiodide, hydroxide, hydroxybenzoate, hydroxynaphthoate, iodide, isethionate, isothionate, l-aspartate, l-camsylate, l-lactate, lactate, lactobionate, laurate, laurylsulphonate, lithium, magnesium, malate, maleate, malonate, mandelate, meso-tartrate, mesylate, methanesulfonate, methylbromide, methylnitrate, methylsulfate, mucate, myristate, N-methylglucamine ammonium salt, napadisilate, naphthylate, napsylate, nicotinate, nitrate, octanoate, oleate, orotate, oxalate, p-toluenesulfonate, palmitate, pamoate, pantothenate, pectinate, persulfate, phenylpropionate, phosphate, phosphateldiphosphate, picrate, pivalate, polygalacturonate, potassium, propionate, pyrophosphate, saccharate, salicylate, salicylsulfate, sodium, stearate, subacetate, succinate, sulfate, sulfosaliculate, sulfosalicylate, suramate, tannate, tartrate, teoclate, terephthalate, thiocyanate, thiosalicylate, tosylate, tribrophenate, triethiodide, undecanoate, undecylenate, valerate, valproate, xinafoate, and the like. (See Berge, et al., J. Pharm. Sci. 1997, 66, 1-19.)

[0356]

[0193] A disclosed complex can exist in solid or liquid form. In the solid state, the complex may exist in crystalline or noncrystalline form, or as a mixture thereof. The skilled artisan will appreciate that pharmaceutically acceptable solvates may be formed for crystalline or non-crystalline complexes. In crystalline solvates, solvent molecules are incorporated into the crystalline lattice during crystallization. Solvates may involve non-aqueous solvents such as ethanol, isopropanol, acetonitrile, DMSO, acetic acid, ethanolamine, or ethyl acetate, or they may involve water as the solvent that is incorporated into the 2025-12-15 crystalline lattice. Solvates wherein water is the solvent incorporated into the crystalline lattice are typically referred to as “hydrates.” Hydrates include stoichiometric hydrates as well as compositions containing variable amounts of water. The disclosure includes all such solvates.

[0357]

[0194] The active agents and complexes described herein may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-; or the molecule as a whole may be defined by optical activity, using (-)- and (+)-, or (D)- and (L)- notation. The disclosure includes all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. For example, in embodiments wherein a complex comprises MDMA, the MDMA may be (R)-MDMA or (S)-MDMA, or a racemic or non-racemic mixture thereof. Stereoisomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. Various methods are known in the art for preparing optically active forms and determining activity. Such methods include standard tests described herein and other similar tests which are well known in the art. Examples of methods that can be used to obtain stereoisomers of the active agents and complexes include selective crystallization, enzymatic resolution, asymmetric synthesis (including asymmetric chemical synthesis and asymmetric enzymatic synthesis), kinetic resolution, and chiral chromatography (including chiral liquid chromatography, gas chromatography, and high-performance liquid chromatography). When an active agent contains olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the disclosure includes both E and Z geometric isomers, as well as mixtures thereof. Likewise, tautomeric forms are included. Certain disclosed complexes may also exhibit atropisomerism (axial chirality) arising from restricted rotation about one or more chemical bonds. Accordingly, each atropisomeric form, as well as mixtures thereof, is included in the disclosure.

[0358]

[0195] The disclosure also includes complexes with at least one desired isotopic substitution of an atom, at an amount above the natural abundance of the isotope, i.e., isotopically enriched. Isotopes are atoms having the same atomic number but different mass numbers, i.e., the same number of protons but a different number of neutrons. Examples of isotopes that can be incorporated into disclosed complexes include isotopes of hydrogen, carbon, nitrogen, oxygen, and chlorine such as2H,3H,11C,13C,14C,15N,17O,180, and36CI respectively. In one non-limiting embodiment, isotopically labeled complexes can be used in metabolic studies (with14C), reaction kinetic studies (with, e.g.,2H or3H), detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays, or in radioactive treatment of patients. An18F-labeled complex may be particularly desirable for PET or SPECT studies. Further, substitution with heavier isotopes such as deuterium, i.e.,2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements. Isotopically labeled complexes can generally be prepared by carrying out the procedures disclosed in the schemes or 2025-12-15 in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent.

[0359]

[0196] The skilled artisan will further appreciate that certain complexes described herein that exist in crystalline form, including the various solvates thereof, may exhibit polymorphism (i.e. the capacity to occur in different crystalline structures). These different crystalline forms are typically known as “polymorphs.” The subject matter disclosed herein includes such polymorphs. Polymorphs include the different crystal packing arrangements of the same elemental composition of a compound or complex. Polymorphs have the same chemical composition but differ in packing, geometrical arrangement, and other descriptive properties of the crystalline solid state. Polymorphs, therefore, may have different physical properties such as shape, density, hardness, deformability, stability, and dissolution properties. Polymorphs typically exhibit different melting points, IR spectra, and X-ray powder diffraction patterns, which may be used for identification. The skilled artisan will appreciate that different polymorphs may be produced, e.g., by changing or adjusting the reaction conditions or reagents, used in making the complex. For example, changes in temperature, pressure, or solvent may result in polymorphs. Various factors such as the recrystallization solvent, rate of crystallization, and storage temperature may cause a single crystal form to dominate. In addition, one polymorph may spontaneously convert to another polymorph under certain conditions.

[0360]

[0197] Crystalline forms of a disclosed complex may have different physical and / or chemical properties, and these may vary in ways relevant for drug delivery. In some cases, a single complex can exist as one or more unique crystalline forms called polymorphs. The different polymorphic forms of a complex may have varying properties related to or that effect, for example, particle size, filtration rates, hygroscopicity, ability to micronize, stability, dissolution rates, dispersibility in powders, and bioavailability. Providing a disclosed complex as a specific polymorph thus may improve any one or more of these properties. It also may improve the therapeutic utility of the complex, for example if the agent has intrinsic barriers to drug delivery, such as low aqueous solubility, slow dissolution in gastrointestinal media, low permeability, or susceptibility to first-pass metabolism.

[0361]

[0198] In embodiments, improved properties may include physical properties, such as melting point, flowability, and / or stability, such as thermal stability, mechanical stability, shelf life, stability against polymorphic transition, etc. In embodiments, advantageous properties may include, but are not limited to, chemical properties, such as hygroscopic properties, solubility in water and / or organic solvents, reactivity, compatibility with excipients and / or delivery vehicles; and / or pharmacokinetic properties, such as bioavailability, absorption, distribution, metabolism, excretion, toxicity including cytotoxicity, dissolution rate, and / or half-life.

[0362]

[0199] Generally, a complex will be administered as part of a pharmaceutical composition or formulation, and is prepared for inclusion in such composition or formulations as an isolated or purified 2025-12-15 complex. The terms “isolated,” “purified,” or “substantially pure,” as used herein, refer to material that is substantially or essentially free from components that normally accompany the material when the material is synthesized, manufactured, or otherwise produced. An “isolated,” “purified,” or “substantially pure” preparation of a complex is accordingly defined as a preparation having a chromatographic purity (of the desired complex) of greater than 90%, greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, greater than 99.5%, or greater than 99.9%, as determined by area normalization of an HPLC profile or other similar detection method.

[0363]

[0200] Preferably the substantially pure complex used in the disclosure is substantially free of any other active compounds which are not intended to be administered to a subject. In this context “substantially free” can be taken to mean that no active compound(s) other than the complex intended to be administered to a subject are detectable by HPLC or other similar detection method, or are below a desired threshold of detection such as defined above.

[0364] C. Methods of Preparing Complexes

[0365]

[0201] In general, complexes can be synthesized using known techniques in synthetic inorganic and organic chemistry (see Example 2). Provided embodiments and schemes are further illustrative of exemplary methods. The specific steps of the provided methods may be described in a particular order as part of exemplary suitable sequences for preparing disclosed complexes. However, a person of ordinary skill in the art will appreciate that the disclosed methods may be modified, rearranged, or adapted, and that steps may be performed in a different order, omitted, or supplemented with additional steps, while still achieving the preparation of complexes within the scope of the present disclosure. A person of ordinary skill, relying on the teachings set forth herein together with general knowledge in the field of synthetic chemistry and coordination chemistry (see, e.g., Garnovskii & Kharissov. 2003. Synthetic Coordination and Organometallic Chemistry, CRC Press, Boca Raton, FL; Lawrence, GA. 2010. Introduction to Coordination Chemistry, John Wiley & Sons, West Sussex, UK), can readily implement alternative sequences and employ equivalent reagents, intermediates, solvents, and equipment as needed to prepare and purify the complexes without departing from the scope of the disclosure.

[0366]

[0202] In embodiments, a complex is obtained by solution-phase complexation. In embodiments, the metal salt and active agent are each dissolved in separate solutions, which are subsequently combined to produce a single mixed solution. In other embodiments, the metal salt and active agent are concurrently dissolved in the same container to generate a single homogeneous or heterogeneous solution.

[0367]

[0203] One or more solvents may be used. The selection of suitable solvent(s) is routine for a skilled artisan, in consideration of the solubility of the starting materials, the desired oxidation state of the metal center, the expected binding mode(s) of the active agent, and process-related considerations such as scalability, solvent compatibility, and the desired physical form of the final complex (e.g., crystalline or non-crystalline). 2025-12-15

[0204] Suitable solvents may include water, alcohols (e.g., methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, benzyl alcohol, ethylene glycol, propylene glycol, glycerol), ketones (e.g., acetone, methyl ethyl ketone, methyl isobutyl ketone, cyclohexanone), esters (e.g., ethyl acetate, methyl acetate, isopropyl acetate, butyl acetate, lactones), ethers (e.g., diethyl ether, diisopropyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, dioxane, tert-butyl methyl ether, diglyme, triglyme, polyethylene glycols), hydrocarbons (e.g., hexane, heptane, octane, petroleum ether, cyclohexane, toluene, xylene, mesitylene, decalin), halogenated solvents (e.g., dichloromethane, chloroform, 1,2-dichloroethane, chlorobenzene, dichlorobenzene, fluorinated hydrocarbons), nitriles (e.g., acetonitrile, propionitrile, benzonitrile), amides (e.g., N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2-pyrrolidone), sulfoxides and sulfones (e.g., dimethyl sulfoxide, sulfolane), carboxylic acids (e.g., acetic acid, formic acid, trifluoroacetic acid), bases (e.g., pyridine, lutidines, collidines, triethylamine, diisopropylethylamine), supercritical fluids (e.g., supercritical CO2), and combinations thereof. Coordinating solvents (e.g., water, alcohols, amides, sulfoxides, nitriles) may participate in metal coordination.

[0368]

[0205] The solution(s) may be prepared under ambient conditions (e.g., open air, ambient moisture, ambient temperature), or under heating or cooling, inert atmosphere, reduced pressure, or controlled-humidity conditions. Complexation may occur upon mixing or may be facilitated by gradual evaporation of solvent, diffusion of an antisolvent, or adjustment of pH, ionic strength, or temperature. The resulting complex may be isolated by filtration, centrifugation, decanting, solvent removal, or drying.

[0369]

[0206] In embodiments, a complex is obtained via hydrothermal or solvothermal synthesis, wherein the metal salt and active agent are combined as a homogeneous or heterogeneous mixture of reactants and solvents at room temperature, sealed in a pressure-resistant vessel (e.g., glass-lined, steel, or Teflon-lined), and heated to an elevated temperature (e.g., 50-250 °C) before cooling to ambient temperature. The resulting solution or slurry can be filtered, decanted, or dried to yield the complex in solid form.

[0370]

[0207] In embodiments, a complex is obtained by mechanochemical synthesis, wherein the metal salt and active agent are combined as solids and exposed to mechanical force sufficient to initiate or promote complex formation. Suitable means for producing mechanical force include physical grinding (e.g., with a mortar and pestle), vibrational milling, planetary ball milling, or twin-screw extrusion. Grinding may be performed neat (i.e., without added solvent) or with liquid-assisted grinding in the presence of a solvent. Solid material obtained from grinding may be subjected to post-grinding processing such as drying, aging, annealing, slurry treatment, or recrystallization.

[0371]

[0208] Crystalline forms of a disclosed complex may be formed through a variety of crystallization techniques readily apparent to the skilled artisan. Exemplary crystallization techniques include, slow evaporation crystallization, cooling crystallization, antisolvent crystallization, vapor diffusion crystallization, 2025-12-15 sublimation crystallization, hydrothermal crystallization, ultrasonic crystallization, gel-growth crystallization, layered solution crystallization, liquid-liquid diffusion crystallization, and microbatch crystallization.

[0372]

[0209] The complexes may be characterized by a variety of analytical techniques that investigate physical structure, thermal properties, stability, and chemical purity. In addition to visual assessment, analytical tools may include X-ray diffraction techniques (e.g., single-crystal X-ray diffraction, powder X-Ray diffraction), thermogravimetric analysis, dynamic scanning calorimetry, microscopy (e.g., optical microscopy, electron microscopy, scanning electron microscopic, transmission electron microscopy), infrared spectroscopy (e.g., Fourier-transform infrared spectroscopy), dynamic vapor sorption, chromatography (e.g., high-performance liquid chromatography), and nuclear magnetic resonance spectroscopy (e.g.,1H NMR,13C NMR).

[0373]

[0210] The metal used in any disclosed method of preparing complexes can be a metal salt, metal complex, or any other metal compound capable of directly or indirectly providing a coordinatively active metal center available for coordination to one or more active agents under the selected reaction conditions. Examples of suitable metal-containing precursors include metal halides, metal nitrates, metal sulfates, metal acetates, metal carbonates, metal hydroxides, metal oxides, metal alkoxides, metal ammines, metal aquo complexes, metal chelates, and metal coordination complexes. The selection of an appropriate metal-containing precursor is within the routine capabilities of one of skill, and may be based on factors including the desired oxidation state of the metal, ligand exchange kinetics, solubility in the chosen solvent system, compatibility with the active agent, and the intended coordination environment of the final complex.

[0374] D. Properties of Metal-Drug Complexes

[0375]

[0211] Disclosed complexes may exhibit properties that differ from those of a comparator, such as the constituent active agent. In embodiments, the comparator is MDMA. In embodiments, the comparator is an MDMA-AA.

[0376]

[0212] Typically, administration of a drug results in rapid systemic availability determined primarily by absorption rate, first-pass metabolism (for oral administration), tissue distribution, and metabolic or renal clearance. For many small-molecule drugs, including MDMA, plasma concentrations rise quickly, often producing an early, sharp maximum concentration followed by a relatively rapid decline in exposure. Prodrugs may alter these kinetics to some extent; however, such approaches generally rely on a single chemical or enzymatic cleavage event to release the free drug, and therefore provide only limited tunability of pharmacokinetics.

[0377]

[0213] By contrast, subsequent to administration of a disclosed complex, one or more additional chemical processes may modulate the release of the active agent. In embodiments, metal-ligand dissociation (i.e., the separation of the active agent from the metal in vivo, such as through dissociation of 2025-12-15 one or more coordinating interactions) is a rate-limiting step that alters (e.g., slows) the release of the active agent.

[0378]

[0214] Furthermore, in embodiments wherein a complex comprises an amino acid drug conjugate (e.g., MDMA-AA), drug release may proceed through multiple sequential events, including (1) metal-ligand dissociation (i.e., dissociation of the MDMA-AA from the metal), and (2) subsequent cleavage of the amino acid moiety from the MDMA-AA to generate free MDMA. Each step may exhibit a distinct rate constant, which may be independently controlled through the chemical structure of the complex (e.g., the choice of metal, amino acid, coordinating interactions).

[0379]

[0215] In embodiments, metal-ligand dissociation (i.e., dissociation of an amino acid moiety from a metal center) and dissociation of an active agent from an amino acid moiety (e.g., hydrolysis of MDMA-AA) occur sequentially or concurrently. In embodiments, metal-ligand dissociation occurs more rapidly than dissociation of the active agent from the amino acid moiety, such that the MDMA-AA is released prior to cleavage of the amino acid moiety. In other embodiments, dissociation of the active agent from the amino acid moiety occurs more rapidly than metal-ligand dissociation, such that cleavage of the amino acid moiety occurs while the MDMA-AA remains coordinated to the metal center. In embodiments, metal-ligand dissociation and dissociation of the active agent from the amino acid moiety occur concurrently, e.g., at comparable rates. In embodiments, the overall release profile of the active agent is governed by the relative magnitudes of the metal-ligand dissociation rate constant and the active agent-amino acid dissociation rate constant, which may be independently manipulated through selection of the metal, amino acid, coordination geometry, and coordinating interactions of the complex, and other factors described herein. In one example, MDMA-AAs comprising amino acids with bulky side chains (e.g., tryptophan, phenylalanine, tyrosine) may sterically shield one or more labile bonds of a complex or complex constituent, such as the amide bond between MDMA and an amino acid, reducing the rate of MDMA-AA dissociation by enzymatic cleavage.

[0380]

[0216] Hence, administration of a disclosed complex may result in an altered pharmacokinetic profile, wherein one or more pharmacokinetic parameters (e.g., Cmax, Tmax, AUC, half-life) are modified relative to a comparator. Modified parameters may comprise any of a decrease in Cmax, increase in Tmax, and increase in half-life.

[0381]

[0217] In embodiments, a disclosed complex has reduced clearance relative to a comparator (e.g., MDMA). In embodiments, clearance refers to intrinsic clearance. In embodiments, pharmacokinetic parameters, including intrinsic clearance and half-life, are determined using an in vitro metabolic stability study comprising human liver microsomes. Methods for assessing metabolic stability, such as in vitro clearance and half-life, are described in, e.g., Gajula et al., Drug Metab Rev. 2021;53(3):459-477 and Knights et al., Curr Protoc Pharmacol. 2016;74:7.8.1-7.8.24. Pharmacokinetic parameters may also be determined in vivo, such as in a human, e.g., according to the paradigm described by Brown et al., Clin 2025-12-15 Pharmacokinet. 2017;56(12): 1543-1554. Additionally, identification of metabolites and interactions with CYP enzymes may be performed as described in, e.g., Caspar et al., Drug Test Anal. 2018;10(1 ):184-195. In embodiments, clearance is decreases by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200% relative to the comparator. In embodiments, the half-life of a disclosed complex is increased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200% relative to the comparator.

[0382]

[0218] In embodiments, coordination to a metal center alters the spatial distribution of the complex (i.e., partitioning between different tissues, such as between the brain and the periphery) relative to a comparator. Such changes in spatial distribution may result from differences in molecular properties between the complex and the comparator (e.g., charge, hydrodynamic radius, logP / logD, polarity, coordination geometry), which may influence tissue distribution, such as by changes in permeability and consequently passive transport across membranes. For example, complexes comprising active agents with lipophilic amino acids (e.g., wherein R is alkyl, particularly C6+alkyl, alkylene-aryl, etc.) may improve the membrane permeability of the complex.

[0383]

[0219] The permeability, such as apparent permeability, of a compound or complex describes how effectively it can pass through a biological membrane (e.g., lipid bilayer, cellular). Measures of permeability can include, for example, apparent permeability coefficient (Papp), effective permeability (Peff), partition coefficient (LogP) / distribution coefficient (LogD), transcellular permeability and paracellular permeability. Methods for determining a measure of permeability, such as in vitro methods, are available to one of skill in the art and include, e.g., a Madin-Darby canine kidney cell line (MDCK) permeability assay and a parallel artificial membrane permeation assay (PAMPA). For example, PAMPA is an in vitro model of passive diffusion, which has shown a high degree of correlation with permeation across a variety of barriers, including Caco-2 cultures, the gastrointestinal tract, blood-brain barrier, and skin. See, e.g., Chavda & Shah, Chapter 25 - Self-emulsifying delivery systems: one step ahead in improving solubility of poorly soluble drugs, In Micro and Nano Technologies, Nanostructures for Cancer Therapy, Elsevier, 2017, pages 653-718.

[0384]

[0220] In embodiments, a disclosed complex has increased permeability relative to a comparator (e.g., MDMA). In embodiments, permeability is increased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 100%, 125%, 150%, or 200% relative to the comparator.

[0385]

[0221] Additionally, certain complexes may exhibit altered spatial distribution because of active transport mechanisms. Certain complexes comprising amino acid drug conjugates (e.g., MDMA-AAs) may interact as substrates with one or more amino-acid transport systems, including neutral, basic, or acidic amino acid transporters, heteromeric amino acid exchangers, or peptide transporters, which may facilitate 2025-12-15 or modulate transport across intestinal, renal, endothelial, or blood-brain barrier membranes. Spatial distribution may also be influenced by endogenous metal-trafficking pathways, wherein biologically relevant metals are subject to regulated transport, sequestration, and buffering processes mediated by metal-binding proteins, metallothioneins, and transferrins.

[0386]

[0222] Spatial distribution may be assessed using standard in vitro, ex vivo, and in vivo methods, including measurement of plasma-to-tissue or blood-to-brain ratios, determination of apparent volume of distribution, analysis of tissue homogenates by LC-MS / MS, quantitative whole-body autoradiography, microdialysis, or imaging-based biodistribution assays (e.g., PET, SPECT, fluorescence, or radiotracer techniques). In embodiments, a disclosed complex exhibits an altered blood:brain ratio, tissue:plasma ratio, or apparent volume of distribution relative to a comparator. In embodiments, the blood: brain ratio of a disclosed complex is increased or decreased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, 150%, or 200% relative to the comparator. In embodiments, the tissue:plasma ratio for one or more tissues (e.g., brain, liver, kidney, muscle, spleen) is increased or decreased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, or 150%. In embodiments, the apparent volume of distribution (Vd) of a disclosed complex is increased or decreased by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, or 150% relative to the comparator.

[0387]

[0223] Altered spatial distribution of complexes relative to comparators may confer improvements in safety, tolerability, and / or therapeutic index. Certain active agents that target neurotransmitter receptors in the brain exhibit adverse effects resulting from engagement of receptors, enzymes, or transporters expressed at high levels in peripheral tissues. For example, many phenethylamine serotonin receptor agonists exhibit agonist activity at the serotonin-2B receptor, which is highly expressed in cardiac tissue and has been associated with the development of valvulopathy and other cardiovascular toxicities (Hutcheson et al. Pharmacol Ther. 2011;132(2): 146-157). Conventional medicinal chemistry approaches generally address such risks in lead optimization by redesigning the drug to reduce off-target activity. By contrast, administration of disclosed complexes may result in reduced peripheral activity, not by altering the active agent’s chemical structure and intrinsic receptor activity profile, but by modulating its spatial distribution, such as by enhanced delivery to the central nervous system and / or reduced accumulation in peripheral tissues. In embodiments, such modulation of spatial distribution decreases peripheral exposure and / or reduces off-target activity, thereby improving overall safety (e.g., therapeutic index) without requiring modification of the core active agent pharmacophore.

[0388]

[0224] In embodiments, a disclosed complex exhibits antioxidant or redox-modulating properties. In embodiments, an antioxidant effect is a direct effect of the inherent redox behavior of one or more components of the complex, such as the metal center, the amino acid moiety, or the complex as a whole (e.g., through radical scavenging and / or redox buffering). In embodiments, an antioxidant effect is an indirect effect, such as through mitigation of drug-induced dysfunction in metal homeostasis and / or 2025-12-15 correction of metal deficiency contributing to oxidative stress, or alteration of pathways that regulate cellular redox balance.

[0389]

[0225] Regarding zinc specifically, Zn(ll) can act as a potent antioxidant in the brain through a variety of means including control of oxidant generation and metal-induced oxidative damage, and controlling redox signaling by altering enzyme activity, binding interactions, and molecular chaperone activity (Baltaciet al. Biol Trace Elem Res. 2018;183:22-31; Maret Antioxid Redox Signal.

[0390] 2006;8(9-10):1419-1441 ). Without being bound by theory, administering a disclosed complex comprising zinc may reduce oxidative stress effects of drugs such as MDMA.

[0391]

[0226] Regarding iron specifically, iron ions are essential to many key biological processes including oxygen transport, cellular respiration, energy production, cell growth and differentiation, and DNA synthesis (Ferreira et al. Pharmaceuticals (Basel). 2019; 12(3): 126). Disrupted iron homeostasis is associated with impairments in various dimensions of brain health including motor function, cognition, and social behavior (Kim et al. J Nutr Biochem. 2014;25(11 ):1101-1107). Iron further plays a significant role in the synthesis of monoamine neurotransmitters, such as serotonin and dopamine. Without being bound by theory, administering a disclosed complex comprising zinc may reduce drug-induced monoamine neurotransmitter depletion, such as that which can occur when MDMA is administered.

[0392]

[0227] Additionally, certain complexes comprise ligands (e.g., MDMA-AAs comprising cysteine, a cysteine derivative, or N-acetylcysteine) that may also exert an antioxidant effect (e.g., through thiol-based radical quenching, redox cycling, or glutathione-associated pathways).

[0393]

[0228] In embodiments, administration of a complex provides a stronger or more effective antioxidant effect than coadministration of the constituent active agent along with a separately administered antioxidant compound (e.g., a zinc salt or zinc complex, or an organic antioxidant compound such as NAC or ascorbate). Without being bound by theory, when an antioxidant component is incorporated into the same complex as the active agent, the antioxidant may be carried along with the active agent during distribution in vivo. In other words, a complex may comprise both a drug payload (i.e., the active agent) and an antioxidant payload (e.g., an antioxidant metal or an organic antioxidant moiety). This may result in delivery of the antioxidant to tissues and cellular environments into which the active agent partitions, thereby increasing local antioxidant availability at sites of active agent action, thereby reducing adverse effects associated with oxidative stress to a greater extent than separate administration of an antioxidant.

[0394]

[0229] In one example, a complex comprises an antioxidant metal (e.g., Zn). In another example, a complex comprises an organic antioxidant moiety (e.g., NAC). In yet another example, a complex comprises both an antioxidant metal and an organic antioxidant moiety. In embodiments, a complex comprises Zn and NAC. In embodiments, a complex comprises Zn and one or more MDMA-AAs comprising NAC. In embodiments, a complex comprises Zn, one or more MDMA-AAs (each of which may 2025-12-15 or may not comprise an organic antioxidant moiety), and one or more molecules of NAC also coordinated to the Zn.

[0395]

[0230] Redox activity and antioxidant effects may be assessed using standard in vitro assays, including ferric reducing antioxidant power (FRAP), oxygen radical absorbance capacity (ORAC), DPPH scavenging, hydroxyl radical scavenging, and cellular ROS quantification, as well as in vivo biomarker measurements such as protein oxidation and glutathione status. In embodiments, administration of a disclosed complex results in reduced formation of ROS, decreased oxidative damage indicators, or increased antioxidant capacity by about or at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 100%, or 150% relative to a comparator. As previously described, the comparator may be MDMA; and / or in embodiments wherein a complex comprises an antioxidant, antioxidant effects may be assessed in comparison to the separate administration of a comparator active agent (e.g., MDMA) along with a comparator antioxidant (e.g., a Zn salt or complex, such as Zn gluconate or ZnSO4; or an organic compound such as NAC).

[0396]

[0231] In embodiments, a disclosed complex exhibits no substantial intrinsic pharmacological activity. In such embodiments, the complex functions primarily as a prodrug, wherein a biological effect arises predominantly or exclusively from release of the constituent active agent following one or more metal-ligand dissociation or promoiety cleavage events as previously described. In other embodiments, a disclosed complex exhibits intrinsic pharmacological activity, which may be distinct from that of the constituent active agent. Such activity may arise from altered molecular properties of the complex (e.g., shape, size, charge, conformational rigidity, electronic distribution, etc.) relative to the constituent active agent, which may influence binding to receptors, transporters, enzymes, ion channels, and other protein targets. Intrinsic activities of complexes can be assessed using standard in vitro or in vivo methods, including radioligand binding assays, functional activity assays (to measure, e.g., agonism, antagonism, partial agonism, inverse agonism), transporter uptake or inhibition assays, enzyme inhibition assays, and other conventional pharmacodynamic evaluation methods.

[0397]

[0232] In embodiments, a disclosed complex exhibits bulk physical properties that differ from those of the constituent active agent. Such differences may include properties relevant to packaging, handling, and formulation, such as crystal structure or polymorphic form, particle size or morphology, flowability, compressibility, density, hygroscopicity, deliquescence, melting point, and thermal stability. In embodiments, a complex exhibits changes in visual appearance relative to the constituent active agent, including alterations in coloration. Metal-ligand complexes are known to exhibit characteristic colors depending on the electronic structure of the metal center. Disclosed complexes may therefore have a color associated with a constituent metal, depending on its oxidation state and ligand interactions, including, for example, purple or violet (e.g., for certain Co(ll) or Mn(lll) complexes), blue (e.g., for certain Cu(ll) complexes), green (e.g., for certain Ni(ll) or Cr(lll) complexes), yellow or orange (e.g., for certain Fe(lll) or 2025-12-15 Mo(VI) complexes), red (e.g., for certain Co(lll) or Fe(ll) complexes), and brown or black hues (e.g., for certain high-valency Mn or Fe complexes). Colors may vary depending on coordination number, ligand identity, metal geometry, counterions, solvation, and solid-state packing.

[0398] E. Pharmaceutical Compositions

[0399]

[0233] In another aspect, provided are pharmaceutical compositions comprising a disclosed complex, and methods of preparing such compositions. A “pharmaceutical composition” is a composition comprising a compound, such as a disclosed complex, and one or more pharmaceutically acceptable excipients, such as carriers, diluents, binders, stabilizers, preservatives, and other formulation aids and inactive ingredients known to those of skill in the art. Such compositions can be prepared by standard techniques such as disclosed in e.g., in Remington's Pharmaceutical Sciences, Mack Publishing Company, Philadelphia, Pa., 20th ed. (2000).

[0400]

[0234] The term “pharmaceutically acceptable” denotes ingredients that are generally safe and, within sound medical judgment, suitable for human or animal use without undue toxicity, irritation, allergic response, or complications, considering a reasonable risk-benefit ratio. Although the term “pharmaceutical” is used, it will be appreciated that the term simply means that a composition is contemplated or shown to possess therapeutic or beneficial effects when administered for its intended purpose to a subject. It therefore will be understood that the disclosed compositions are useful regardless of the regulatory regime under which they are ultimately sold, and also if not sold under a specific regulatory regime at all, whether in the U. S. or any other country. It also will be understood that the disclosed compositions and formulations may be considered to have or to provide therapeutic or beneficial effects whether or not they are marketed in any jurisdiction (or capable of being marketed in any jurisdiction, under any applicable regulatory regime) as having such.

[0401]

[0235] In embodiments, the pharmaceutical composition comprises a binder. Binders include, for example, povidone, microcrystalline cellulose, hydroxypropyl methylcellulose, starch, gelatin, polyethylene glycol, pregelatinized starch, and carbomers. In embodiments, the pharmaceutical composition comprises a binder at a concentration of about 1 % to 10% w / w.

[0402]

[0236] In embodiments, the pharmaceutical composition comprises a diluent. Diluents include, for example, lactose, mannitol, microcrystalline cellulose, starch, calcium phosphate, sorbitol, sucrose, and dextrose. In embodiments, the pharmaceutical composition comprises one or more diluents at a total concentration of about 5% to 80% w / w with respect to the total weight of the composition.

[0403]

[0237] In embodiments, the pharmaceutical composition comprises a disintegrant. Disintegrants include, for example, croscarmellose sodium, sodium starch glycolate, crospovidone, alginic acid, carboxymethylcellulose, and ion-exchange resins. In embodiments, the pharmaceutical composition comprises one or more disintegrants at a total concentration of about 2% to 10% w / w with respect to the total weight of the composition. 2025-12-15

[0238] In embodiments, the pharmaceutical composition comprises a carrier. Carriers include, for example, lactose, cellulose, starch, mannitol, sorbitol, microcrystalline cellulose, magnesium stearate, and polyvinylpyrrolidone (PVP). In embodiments, the pharmaceutical composition comprises one or more carriers at a total concentration of between about 1% and 95% w / w with respect to the total weight of the composition.

[0404]

[0239] In embodiments, the pharmaceutical composition comprises a pH adjuster. pH adjusters include, for example, sodium hydroxide, potassium hydroxide, hydrochloric acid, citric acid, acetic acid, phosphoric acid, sodium bicarbonate, sodium carbonate, and ammonium hydroxide. In embodiments, the pharmaceutical composition comprises one or more pH adjusters at a total concentration of between about 0.01 % and 10% w / w with respect to the total weight of the composition.

[0405]

[0240] In embodiments, the pharmaceutical composition comprises a thickener. Thickeners include, for example, hydroxypropyl methylcellulose (HPMC), carboxymethyl cellulose (CMC), xanthan gum, guar gum, alginates, polyvinyl alcohol (PVA), and methylcellulose. In embodiments, the pharmaceutical composition comprises one or more thickeners at a total concentration of between about 0.1 % and 10% w / w with respect to the total weight of the composition.

[0406]

[0241] In embodiments, the pharmaceutical composition comprises an emulsifier. Emulsifiers include, for example, polysorbate 80, lecithin, cetyl alcohol, stearyl alcohol, sorbitan esters, polyoxyethylene stearates, and glycerin monostearate. In embodiments, the pharmaceutical composition comprises one or more emulsifiers at a total concentration of between about 0.1% and 5% w / w with respect to the total weight of the composition.

[0407]

[0242] In embodiments, the pharmaceutical composition comprises a lubricant. Lubricants include, for example, magnesium stearate, stearic acid, talc, calcium stearate, zinc stearate, polyethylene glycol, and sodium stearyl fumarate. In embodiments, the pharmaceutical composition comprises one or more lubricants at a total concentration of about 0.25% to 5% w / w with respect to the total weight of the composition.

[0408]

[0243] In embodiments, the pharmaceutical composition comprises a glidant. Glidants include, for example, colloidal silicon dioxide, talc, magnesium trisilicate, and calcium phosphate. In embodiments, the pharmaceutical composition comprises one or more glidants at a total concentration of about 0.1% to 2% w / w with respect to the total weight of the composition.

[0409]

[0244] In embodiments, the pharmaceutical composition comprises a surfactant. Surfactants include, for example, sodium lauryl sulfate, polysorbate 80, poloxamers, lecithin, sorbitan esters, and bile salts. In embodiments, the pharmaceutical composition comprises one or more surfactants at a total concentration of about 0.1 % to 5% w / w with respect to the total weight of the composition.

[0410]

[0245] In embodiments, the pharmaceutical composition comprises a preservative. Preservatives include, for example, benzyl alcohol, parabens (methylparaben, propylparaben), benzoic acid, sorbic acid, 2025-12-15 chlorobutanol, and phenol. In embodiments, the pharmaceutical composition comprises one or more preservatives at a total concentration of about 0.01% to 1% w / w with respect to the total weight of the composition.

[0411]

[0246] In embodiments, the pharmaceutical composition comprises a stabilizer. Stabilizers include, for example, ascorbic acid, citric acid, sodium metabisulfite, tocopherols, tartaric acid, sodium bicarbonate, and phosphates. In embodiments, the pharmaceutical composition comprises one or more stabilizers at a total concentration of about 0.01% to 5% w / w with respect to the total weight of the composition.

[0412]

[0247] In embodiments, the pharmaceutical composition comprises a sweetener or flavoring agent. Sweeteners and flavoring agents include, for example, sucralose, aspartame, saccharin, acesulfame potassium, menthol, vanillin, peppermint oil, and fruit extracts. In embodiments, the pharmaceutical composition comprises one or more sweeteners or flavoring agents at a total concentration of about 0.1 % to 5% w / w with respect to the total weight of the composition.

[0413]

[0248] In embodiments, the pharmaceutical composition comprises a solvent. Preferred solvents are those generally regarded as safe for human use and are commonly used in oral, injectable, and topical formulations. Solvents include, for example, water, ethanol, propylene glycol, polyethylene glycol, glycerin, isopropyl alcohol, butylene glycol, methylparaben, propylparaben, sorbitol, and sodium chloride. In embodiments, the pharmaceutical composition comprises one or more solvents (collectively referred to as a “solvent system”) at a total concentration of between about 0.1 % and 90% with respect to the total weight of the composition, depending on the formulation, properties of the complex, and route of administration.

[0414]

[0249] It should be understood that the classification of excipients into specific categories is for convenience and ease of reference only, and no particular limitation should be inferred based on such classification. A single excipient may serve multiple functions within a pharmaceutical composition, depending on its concentration, formulation, and intended use. For example, microcrystalline cellulose may function as both a binder and a diluent, while sodium lauryl sulfate may act as both a surfactant and a wetting agent. The descriptions provided herein are not intended to be exhaustive, and the selection and use of excipients should be guided by the specific formulation requirements and the knowledge of those skilled in the art.

[0415]

[0250] Pharmaceutical compositions may be administered via various routes, including oral, mucosal (buccal, sublingual), rectal, transdermal, subcutaneous, intravenous (IV), intramuscular, inhaled, and intranasal; and may be formulated specifically for that route of administration. For example, a pharmaceutical composition for oral administration may be formulated as an oral solid or liquid dosage form. As another example, a pharmaceutical composition for intravenous, intramuscular, or subcutaneous administration may be formulated as an IV solution, or a lyophilized powder for reconstitution. All such formulations, as well as unit dosage forms thereof, are included in the disclosure, including: tablets, 2025-12-15 caplets, capsules (such as hard gelatin capsules or soft elastic gelatin capsules), cachets, troches, lozenges, gums, dispersions, suppositories, ointments, cataplasms (poultices), pastes, powders, dressings, creams, solutions, patches, aerosols (e.g., nasal spray or inhalers), gels, suspensions (e.g., aqueous or non-aqueous liquid suspensions, oil-in-water emulsions or water-in-oil liquid emulsions), solutions and elixirs.

[0416]

[0251] In embodiments, such as wherein the pharmaceutical composition is a solid dosage form, the composition comprises a complex at a concentration of between about 0.1% and 90% w / w, including between about 1% and 5% w / w, 5% and 10% w / w, 10% and 20% w / w, 15% and 30% w / w, 20% and 30% w / w, 20% and 40% w / w, 30% and 40% w / w, 30% and 50% w / w, 40% and 60% w / w, 50% and 70% w / w, 60% and 80% w / w, 70% and 80% w / w, 70% and 90% w / w, 80% and 90% w / w, 0.1% and 10% w / w, 10% and 40% w / w, 40% and 80% w / w, and 80% and 90% w / w.

[0417]

[0252] In embodiments, such as wherein the pharmaceutical composition is a liquid dosage form, the composition comprises a complex at a concentration of between about 0.01 mg / mL and 200 mg / mL, including between about 0.01 mg / mL and 0.1 mg / mL, 0.1 mg / mL and 1 mg / mL, 1 mg / mL and 5 mg / mL, 5 mg / mL and 10 mg / mL, 10 mg / mL and 20 mg / mL, 15 mg / mL and 25 mg / mL, 20 mg / mL and 30 mg / mL, 25 mg / mL and 35 mg / mL, 30 mg / mL and 40 mg / mL, 35 mg / mL and 50 mg / mL, 40 mg / mL and 60 mg / mL, 50 mg / mL and 70 mg / mL, 60 mg / mL and 80 mg / mL, 70 mg / mL and 100 mg / mL, 80 mg / mL and 120 mg / mL, 100 mg / mL and 150 mg / mL, 120 mg / mL and 180 mg / mL, 150 mg / mL and 200 mg / mL, and 200 mg / mL and 300 mg / mL.

[0418]

[0253] As will be appreciated by one of skill in the art, the concentration of the complex in the pharmaceutical composition may vary according to the route of administration, desired dose, and pharmacokinetic and pharmacodynamic properties of the complex.

[0419] D. Pharmaceutical Combinations

[0420]

[0254] It should be readily appreciated that the disclosed compositions are not limited to combinations of a single complex, or (when formulated as a pharmaceutical composition) limited to a single carrier, diluent, and / or excipient alone, but may also include combinations of multiple complexes and / or additional active compounds, and / or multiple carriers, diluents, and excipients. Pharmaceutical compositions of this disclosure thus may comprise a disclosed complex together with one or more other active agents (or their derivatives and analogs) in combination, together with one or more pharmaceutically acceptable carriers, diluents, and / or excipients, and additionally with one or more other active compounds.

[0421]

[0255] In embodiments, a formulation of the disclosure will be prepared so as to increase an existing therapeutic effect, provide an additional therapeutic effect, increase a desired property such as stability or shelf-life, decrease an unwanted effect or property, alter a property in a desirable way (such as pharmacokinetics or pharmacodynamics), modulate a desired system or pathway (e.g., a neurotransmitter system), or provide synergistic effects. 2025-12-15

[0256] “Synergistic effects” should be understood to include increases in potency, bioactivity, bioaccessibility, bioavailability, or therapeutic effect, that are greater than the additive contributions of the components acting alone. Numerous methods known to those of skill in the art exist to determine whether there is synergy as to a particular effect, i.e., whether, when two or more components are mixed together, the effect is greater than the sum of the effects of the individual components applied alone, thereby producing “1+1 > 2.” Suitable methods include isobologram (or contour) analysis (Huang, Front Pharmacol., 2019; 10:1222), or the equation of Loewe additivity (Loewe & Muischnek, 1926, Arch. Exp. Pathol Pharmacol. 114: 313-326).

[0422]

[0257] A synergistic effect also may be calculated using methods such as the Sigmoid-Emax equation (Holford & Scheiner, 1981, Clin. Pharmacokinet. 6: 429-453) and the median-effect equation (Chou & Talalay, 1984, Adv. Enzyme Regul. 22:27-55). The corresponding graphs associated with the equations referred to above are the concentration-effect curve and combination index curve, respectively. Each equation referred to above may be applied to experimental data to generate a corresponding graph to aid in assessing the effects of the drug combination.

[0423]

[0258] In embodiments, a disclosed pharmaceutical composition comprises an additional active compound. In embodiments, the additional active compound is selected from the group consisting of: amino acids and amino acid derivatives, analogs, and mimetics, antioxidants, anti-inflammatory agents, neuroprotective agents, analgesic, antinociceptive, antineuropathic agents, anxiolytic agents, antidepressant agents, anti-PTSD agents, empathogenic (entactogenic) agents, psychedelic agents, dissociative agents, psychoplastogenic or plasticity-inducing agents, monoaminergic agents, serotonergic agents, monoamine oxidase inhibitors, nootropic and pro-cognitive agents, sedative or calming agents, stimulant or wake-promoting agents, cannabinoids, terpenes, and vitamins.

[0424]

[0259] In embodiments, the additional active compound acts to increase a therapeutic effect, provide an additional therapeutic effect, decrease an unwanted effect, increase stability or shelf-life, improve bioavailability, induce synergy, increase plasticity (e.g., neural plasticity), or alter pharmacokinetics or pharmacodynamics. In embodiments, the additional therapeutic effect is an antioxidant, anti-inflammatory, analgesic, antineuropathic, antinociceptive, antimigraine, anxiolytic, antidepressant, antipsychotic, anti-PTSD, dissociative, immunostimulant, anti-cancer, antiemetic, orexigenic, antiulcer, antihistamine, antihypertensive, anticonvulsant, antiepileptic, bronchodilator, neuroprotective, empathogenic, psychedelic, sedative, or stimulant effect.

[0425]

[0260] In embodiments, an additional active compound is a supplement commonly taken in combination with MDMA. As will be known to those of skill in the art, many supplement combinations (i.e., “stacks”) are used by subjects who seek to minimize the adverse effects of MDMA (see, e.g., Psychedelic Support. (2024, March 28). Supplements to reduce side effects of MDMA. Supplements to Reduce Side Effects of MDMA ■ Psychedelic Support). In embodiments, the supplement is any of alpha lipoic acid, 2025-12-15 acetyl-L-carnitine, N-acetylcysteine, magnesium, zinc, vitamin C, vitamin E, nicotinamide, melatonin, omega-3-fatty acids, grape seed extract, green tea extract, ginger, Co-Q10, 5-hydroxytryptophan, epigallocatechin gallate, and electrolytes, or a combination thereof.

[0426]

[0261] In embodiments, an additional active compound is a tryptamine. As understood by those in the art, tryptamines are compounds having the general structure below, wherein RN1, RN2, R°, Rp, R2, R4, R5, R6, and R7are as generally understood in the art:

[0427] RP R I INRN2

[0428]

[0429]

[0262] Exemplary tryptamines that may be combined with a disclosed complex include psilocybin, psilocin, psilacetin, DBT, DET, DiPT, a, O-DMS, DMT, 2,a-DMT, a, N-DMT, DPT, EiPT, AET, 4-HO-DBT, 4-HO-DET, 4-HO-DiPT, 4-HO-TMT, 4-HO-DMT, 5-HO-DMT (i.e., bufotenine), 4-HO-DPT, 4-HO-MET, 4-HO-MiPT, 4-HO-MPT, 4-HO-pyr-T, ibogaine, MBT, 4,5-MDO-DiPT, 5,6-MDO-DiPT, 4,5-MDO-DMT, 5.6-MDO-DMT, 5,6-MDO-MiPT, 2-Me-DET, 5-Br-DMT, 5-CI-DMT, 5-F-DMT, 4,5-MDO-DMT, 4,5-MDO-DiPT, 2-Me-DMT, melatonin, 5-MeO-DET, 5-MeO-DiPT, 5-MeO-DALT, 5-MeO-DMT, 4-MeO-MiPT, 5-MeO-MiPT, 5.6-MeO-MiPT, 5-MeO-NMT, 5-MeO-pyr-T, 5-MeO-TMT, 5-MeS-DMT, MiPT, a-MT (i.e., AMT), NET, NMT, pyr-T, tryptamine, and a, N, O-TMS, or a pharmaceutically acceptable salt, solvate, prodrug, isotopolog, stereoisomer, or tautomer thereof, or a combination thereof. As known to one of skill, the systematic naming of tryptamines, such as those listed herein, involves the use of prefixes and suffixes to indicate substitutions on the indole ring and / or the side chain of the tryptamine core structure. For example, EiPT stands for ethyl isopropyl tryptamine, also known as N-ethyl-N-isopropyltryptamine (i.e., N-ethyl-N-[2-(1 H-indol-3-yl)ethyl] propan-2-amine). Examples of these tryptamines and others that may in embodiments be included in a disclosed composition as an additional active compound are known to those of skill, and include the compounds disclosed in Shulgin & Shulgin, TiHKAL: The Continuation, Transform Press (1997) (“TiHKAL”).

[0430]

[0263] In embodiments, an additional active compound is a phenylalkylamine. In embodiments, the phenylalkylamine is a compound of Formula (A). Exemplary phenylalkylamines that may be combined with a disclosed complex include mescaline, a-ethylmescaline, escaline, symbescaline, metaescaline, allylescaline, methallylescaline, asymbescaline, cyclopropylmescaline, phenescaline, 4-desoxymescaline, isomescaline, proscaline, metaproscaline, isoproscaline, thiomescaline, thioescaline, thioproscaline, thiobuscaline, a thiomescaline analog (e.g., 3-TM, 4-TM), buscaline, a thioisomescaline (e.g., 2-TIM, 3-TIM, 4-TIM), Aleph (i.e., DOT), a thiometaescaline (e.g., 3-TME, 4-TME, 5-TME), a thiotrisescaline (e.g., 3-T-TRIS, 4-T-TRIS), a thiosymbescaline (e.g., 3-TSB, 4-TSB), Aleph-2, Aleph-4, Aleph-6, Aleph-7, 2025-12-15 Ariadne, Beatrice (i.e., MDO-D, MDOM), BIS-TOM, BOB, BOD, BOH, BOHD, BOM, 4-Br-3,5-DMA, 2-Br-4,5-MDA, MDEA, 3C-BZ, a 2C-X compound (e.g., 2C-B, 2C-B-AN, 2C-B-FLY, 2C-B-BUTTERFLY, 2C-B-FLY-NB0Me, 2C-Bn, 2C-Bu, 2C-B-5-hemiFLY, 20-0, 2C-C-3, 2C-CN, 2C-CP, 2C-D, 2C-E, 2C-EF, 2C-F, 2C-G, 2C-G-1, 2C-G-2, 2C-G-3, 2C-G-4, 2C-G-5, 2C-G-6, 2C-G-N, 2C-H, 2C-I, 2CB-lnd, 2C-iP, 2C-N, 2C-NH2, 2C-PYR, 2C-PIP, 20-0, 2C-O-4, 2C-M0M, 2C-P, 2C-Ph, 2C-Se, 2C-T, 2C-T-2, 2C-T-3, 2C-T-4, 2C-T-5, 2C-T-6, 2C-T-7, 2C-T-8, 2C-T-9, 2C-T-10, 2C-T-11, 2C-T-12, 2C-T-13, 2C-T-14, 2C-T-15, 2C-T-16, 2C-T-17, 2C-T-18, 2C-T-19, 2C-T-21, 2C-T-21.5, 2C-T-22, 2C-T-23, 2C-T-24, 2C-T-25, 2C-T-27, 2C-T-28, 2C-T-30, 2C-T-31, 2C-T-32, 2C-T-33, 2C-DFM, 2C-TFM, 2C-TFE, 2C-YN, 2C-V, 2C-AL, CPM, psi-2C-T-4, 2C-Se), 3C-BZ, 3C-E, 4-D, beta-D, 2,4-DMA, 2,5-DMA, 3,4-DMA, DMCPA, DME, DMMDA, DMMDA-2, DMPEA, DOAM, DOB, DOBU, DOC, DOEF, DOET, DOI, DOM (i.e., STP), psi-DOM, DON, DOPR, EEE, EEM, EME, EMM, ETHYL-J, ETHYL-K, F-2, F-22, FLEA, Ganesha, a Ganesha analog (e.g., G-3, G-4, G-5, G-N), HOT-2, HOT-7, HOT-17, IDNNA, IRIS, BDB, Lopophine, 4-MA (i.e., PMA), MADAM-6, MDA, MDMA, MDAL, MDBU, MDBZ, MDCPM, MDDM, MDE, MDHOET, MDIP, MDMC, MDMEO, MDMEOET, MDMP, MDOH, MDPEA, MDPH, MDPL, MDPR, MEDA, MEE, MEM, MEPEA, meta-DOB, meta-DOT, methyl-DMA, methy-DOB, methyl-J (i.e., MBDB), methyl-K, methyl-MA (i.e., PMMA), METHYL-MMDA-2, MMDA, MMDA-2, MMDA-3a, MMDA-3b, MME, MPM, ortho-DOT, PEA, Propynyl, tetramethoxyamphetamine, 3-TASB, 4-TASB, 5-TASB, 3-TE, 4-TE, TMA, TMA-2, TMA-3, TMA-4, TMA-5, TMA-6, 2T-MMDA-3a, 4T-MMDA-2, TMPEA, 2-TOET, 5-TOET, 2-TOM, 5-TOM, TOMSO, 4-MTA, MDAI, 5-methyl-MDA, 5-APB, 6-APB, and DiFMDA, or a pharmaceutically acceptable salt, solvate, prodrug, isotopolog, stereoisomer, or tautomer thereof, or a combination thereof. As known in the art, the systematic naming of phenethylamines, such as those herein, involves the use of prefixes and suffixes to indicate substitutions on the phenyl ring and / or side chain of the phenethylamine core structure. For example, MDBZ stands for methylenedioxybenzylamphetamine (i.e., 3,4-methylenedioxy-N-benzylamphetamine). Examples of these phenethylamines and others that, in embodiments, may be included in a disclosed composition as an additional active compound are known to those of skill, and include the compounds disclosed in Shulgin & Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991) (“PiHKAL”); and Shulgin AT, The Shulgin Index Vol.1: Psychedelic Phenethylamines & Related Compounds, Transform Press (2011).

[0431]

[0264] In embodiments, an additional active compound is an ergoline. In embodiments, an additional active compound is an ergot alkaloid. In embodiments, an additional active compound is a lysergamide. As understood by those in the art, lysergamides are compounds having the general structure below, wherein RN1, RN2, R1, R2, R4, R6, R7, R8, R9, R12, R13, and R14are as generally understood in the art: 2025-12-15

[0432] RN1rN2

[0433]

[0434]

[0265] Exemplary lysergamides that may be combined with a disclosed complex include LSD, ETH-LAD, PARGY-LAD, AL-LAD, PRO-LAD, IP-LAD, CIP-LAD, BU-LAD, FLUOROETH-LAD, ALD, ALD-52, N-acetyl-LSD, 1P-LSD, 1B-LSD, 1V-LSD, 1cP-LSD, 1D-LSD, 1P-AL-LAD, 1cP-AL-LAD, 1P-ETH-LAD, LA-SS-Az, LSZ, LSD-Pip, 2-Br-LSD, and MIPLA, or a pharmaceutically acceptable salt, solvate, prodrug, isotopolog, stereoisomer, or tautomer thereof, or a combination thereof.

[0435]

[0266] Other tryptamines, phenethylamines, and lysergamides useful as additional active compounds for purposes of the disclosure and thus contemplated for inclusion therein will be as generally known in the art (see, e.g., Shulgin and Shulgin, PiHKAL: A Chemical Love Story, Transform Press (1991); Shulgin and Shulgin, TiHKAL: The Continuation, Transform Press (1997); Grob & Grigsby, Handbook of Medical Hallucinogens, 2021; Luethi & Liechti, Arch. Toxicol., 2020; 94, 1085-1133; Nichols, Pharmacological Reviews, 2016; 68(2), 264-355; Glennon, Pharmacology Biochemistry and Behavior, 1999; 64, 251-256; each of which is incorporated by reference as if fully set forth herein).

[0436] E. Kits

[0437]

[0267] Another aspect of this disclosure provides pharmaceutical kits containing a pharmaceutical composition or formulation of the disclosure, suggested administration guidelines or prescribing information therefor, and a suitable container. Individual unit dosage forms can be included in multi-dose kits or containers. Pharmaceutical formulations also can be packaged in single or multiple unit dosage forms for uniformity of dosage and ease of administration.

[0438]

[0268] Kits generally comprise suitable packaging. The kits may comprise one or more containers comprising any complex described herein. Each component (if there is more than one component) can be packaged in separate containers or some components can be combined in one container where cross-reactivity and shelf life permit. The kits may be in unit dosage forms, bulk packages (e.g., multi-dose packages) or sub- unit doses. For example, kits may be provided that contain sufficient dosages of a complex as disclosed herein and / or an additional active agent useful for a disease detailed herein to provide effective treatment of an individual for an extended period, such as any of a week, 2 weeks, 3 weeks, 4 weeks, 6 weeks, 8 weeks, 3 months, 4 months, 5 months, 7 months, 8 months, 9 months, or 2025-12-15 more. Kits may also include multiple unit doses of the complexes and instructions for use and be packaged in quantities sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0439]

[0269] Information pertaining to dosing and proper administration (if needed) can be printed onto a multi-dose kit directly (e.g., on a blister pack or other interior packaging holding the compositions or formulations of the disclosure); however, kits of the disclosure can further contain package inserts and other printed instructions (e.g., on exterior packaging) for administering the disclosed compositions and for their appropriate therapeutic use.

[0440] F. Methods of Use

[0441]

[0270] In some aspects, provided herein are methods of using the disclosed complexes. In embodiments, disclosed complexes are used to modulate neurotransmission. In embodiments, disclosed complexes are used to treat a medical condition, such as a disease or a disorder. In embodiments, disclosed complexes are used in the manufacture of a medicament for the therapeutic and / or the prophylactic treatment of a medical condition, such as a disease or a disorder. In embodiments, disclosed complexes are administered in a therapeutically effective amount to a subject having a medical condition, such as a disease or a disorder. In embodiments, the medical condition is a disease or disorder linked to dysregulation or inadequate functioning of monoaminergic (e.g., serotonergic, dopaminergic, noradrenergic) neurotransmission. In embodiments, disclosed complexes are administered to a subject that is healthy.

[0442]

[0271] It should be understood that any embodiment referring to the administration or use of a disclosed complex should also be interpreted to encompass the administration or use of a pharmaceutical composition comprising the complex, or a pharmaceutically acceptable salt, stereoisomer, isotopolog, or solvate thereof, unless explicitly stated otherwise.

[0443]

[0272] In embodiments, “treating” or “treatment” refers to treating a disease or disorder in a subject, and includes causing a desired biological or pharmacological effect, such as: (a) inhibiting a disorder, i.e., arresting its development; (b) relieving a disorder, i.e., causing regression thereof; (c) protecting from or relieving a symptom or pathology caused by or related to a disorder; (d) reducing, decreasing, inhibiting, or ameliorating one or more symptoms or pathologies associated with a disorder; and (e) inhibiting or preventing the worsening or progression of symptoms or pathologies associated with a disorder or comorbid with a disorder. Other such measurements, benefits, and surrogate or clinical endpoints, alone or in combination, will be understood by one of skill in view of the teachings herein and the knowledge in the art.

[0444]

[0273] Administration of a complex to a subject in a “therapeutically effective amount,” or an “effective amount” means administration of an amount of the complex or composition sufficient to achieve a desired effect. When an “effective amount” means an amount effective in treating a stated medical 2025-12-15 condition in a subject, “therapeutic effect” would be understood to mean the responses(s) in the subject after treatment that are judged to be desirable and beneficial. Depending on the condition to be treated, or improvement in health or functioning sought, and depending on the particular properties of the complex or composition administered, those responses may differ, but would be readily understood by those of ordinary skill, in view of the disclosure herein and the general knowledge of the art (e.g., by reference to symptoms listed in established diagnostic criteria (e.g., ICD-11) for the stated condition).

[0445]

[0274] The terms “subject,” “user,” “patient,” and “individual” may be used interchangeably herein, and refer to any mammal, although preferably humans. Such terms will be understood to include one who has an indication for which a disclosed complex, composition, or method may be efficacious, or who otherwise may benefit from the invention. In general, all of the disclosed complexes, compositions, and methods will be appreciated to work for all individuals, although individual variation is to be expected, and will be understood.

[0446]

[0275] In embodiments, a patient will participate in a treatment protocol or a disclosed method, or be administered a disclosed composition as part of such a method, if the patient meets certain specified inclusion criteria, does not meet certain specified exclusion criteria, does not meet any specified withdrawal criteria during the course of treatment, and otherwise satisfies the requirements of the embodiment of the disclosure as claimed.

[0447]

[0276] A disclosed complex can be administered to a subject by one or more routes of administration, including, e.g., oral, mucosal, rectal, subcutaneous, intravenous, intramuscular, intranasal, inhaled, ocular, intraocular, topical, and transdermal routes. In embodiments, disclosed complexes are orally bioavailable. In embodiments, disclosed complexes have an oral bioavailability (%F) of about or at least 50%, 60%, 70%, 80%, or 90%. Bioavailability studies, both in vitro measures and in vivo determinations, are described in, e.g., Kim et al., Pharm Res. 2014; 31(4): 1002-1014, EP2007397B1, EP3565550B1, and US20200009067A1.

[0448]

[0277] In embodiments, a unit dose of a complex is (and thus in embodiments, a method comprises administering a complex to a subject at a dose of) about 0.01 mg / kg and about 20 mg / kg (calculated based on the kilogram weight of the patient), including, for example, between about 0.05 mg / kg and about 10 mg / kg, between about 0.1 mg / kg and about 5 mg / kg, between about 0.2 mg / kg and about 3 mg / kg, between about 0.5 mg / kg and about 2 mg / kg, and between about 1 mg / kg and about 1.5 mg / kg. In embodiments, a unit dose of a complex is greater than about 20 mg / kg. In embodiments, a unit dose of a complex is less than about 0.01 mg / kg.

[0449]

[0278] In embodiments, a unit dose of a complex is (and thus in embodiments, a method comprises administering a complex to a subject at a dose of) between about 0.01 mg and about 1000 mg, including, for example, between about 0.1 mg and about 100 mg, between about 1 mg and 1000 mg, between about 0.1 mg and about 500 mg, between about 1 mg and about 400 mg, between about 10 mg 2025-12-15 and about 300 mg, between about 10 mg and about 400 mg, between about 50 mg and about 300 mg, between about 20 mg and about 200 mg, between about 50 mg and about 150 mg, between about 50 mg and about 500 mg, between about 100 mg and about 500 mg, between about 150 mg and about 1000 mg, and between about 200 mg and about 800 mg. In embodiments, a unit dose of a complex is greater than about 1000 mg. In embodiments, a unit dose of a complex is less than about 0.01 mg.

[0450]

[0279] It will be appreciated that dosages may vary depending on factors such as the onset, progression, severity, frequency, duration, or susceptibility of the symptom being treated, the desired clinical endpoint, prior or concurrent treatments, general health, age, gender, and race of the subject, bioavailability, potential adverse side effects (systemic, regional, or local), the presence of other disorders or diseases in the subject, and other factors known to those skilled in the art (e.g., medical or familial history). One skilled in the art, guided by the teachings herein, will understand the factors that influence the dosage, frequency, and timing required to achieve a therapeutic effect or benefit, while also minimizing adverse effects.

[0451]

[0280] In embodiments, the actual dose administered will be determined by a medical provider in consideration of the relevant circumstances, including the disorder being treated (if any), the chosen route of administration, the specific composition or formulation used, the age, weight, and response of the individual subject, and the severity of the subject’s symptoms (if any). As such, any disclosed dosage ranges are not intended to limit the scope of the disclosure. In certain cases, a dosage below the lower limit of a disclosed range may still be effective, while higher doses may be employed without causing harmful side effects, provided that such larger doses may be divided into smaller doses for administration, either together or separately.

[0452] a. Reducing Adverse Effects

[0453]

[0281] MDMA and its metabolites are well known to cause numerous adverse effects in the central nervous system (CNS) and peripheral systems. These effects include stimulating reactive oxygen species (ROS) production by neuronal mitochondria (Costa et al. Exp Neurol. 2022;347:113894), and MDMA use is associated with cardiotoxicity, hepatic damage, and renal failure (Song et al. Curr Pharm Biotechnol. 2010 Aug; 11 (5): 434-43).

[0454]

[0282] In embodiments, administration of a disclosed complex results in reduced adverse effect incidence or severity, as compared to administration of a comparator (e.g., MDMA), in an amount for at least one adverse effect of at least a 5% reduction, at least a 10% reduction, at least a 15% reduction, at least a 25% reduction, at least a 50% reduction, at least a 75% reduction, at least a 90% reduction, at least a 95% reduction, at least a 99% reduction, or a reduction beyond the threshold of measurement, whether determined within-subject or across subjects or subject groups, or in a rodent or other suitable animal model, or determined in vitro, in silico, or otherwise measured using a standard methodology such as one known to those of ordinary skill for the determination or quantification of the adverse event(s) in question, 2025-12-15 such as relating to effects such as inflammation, immunosuppression, oxidative stress, mitochondrial dysfunction, and toxicity (e.g., neurotoxicity, cardiotoxicity, renal toxicity).

[0455]

[0283] A reduction in inflammation can be determined by measuring the change in an inflammation response biomarker in a subject before and after administration of the complex and / or comparator. Inflammation biomarkers and methods for their measurement are known to those of skill in the art, and include, e.g., IL-1β, IL-12, IL-15, IP-10, TNF-α, and the mRNA from which they are produced (see, e.g., O'Shea et al. Neuropharmacology. 2014;87:125-134).

[0456]

[0284] A reduction in immunosuppression can be determined by measuring the change in an immune response biomarker in a subject before and after administration of the complex and / or comparator. Immune response biomarkers and methods for their measurement are known to those of skill in the art, and include, e.g., IL-1β, IL-10, IL-2, TNF-α, circulating CD4+T cells, T cell proliferation, and circulating natural killer (NK) cells (see, e.g., Connor. Immunology. 2004: 111;357-367).

[0457]

[0285] A reduction in oxidative stress can be determined by measuring the change in an oxidative stress biomarker in a subject before and after administration of the complex and / or comparator. Oxidative stress biomarkers and methods for their measurement are known to those of skill in the art, and include, e.g., ROS, ROS-related tissue damage, antioxidant levels, malondialdehyde, F2-isoprostanes, carbonylated proteins, advanced oxidation protein products, 8-hydroxy-2’-deoxyguanosine, superoxide dismutase (8-OHdG), catalase, and glutathione peroxidase (see, e.g., Song et al. Curr Pharm Biotechnol.

[0458] 2010 Aug; 11 (5):434-43).

[0459]

[0286] A reduction in mitochondrial dysfunction can be determined by measuring the change in an mitochondrial dysfunction biomarker in a subject before and after administration of the complex and / or comparator. Mitochondrial dysfunction biomarkers and methods fortheir measurement are known to those of skill in the art, and include, e.g., ATP levels, mitochondrial ROS production, OXPHOS function, mitochondrial membrane potential, mitochondrial swelling, mitochondrial outer membrane damage, the mitochondrial cytochrome c release, ADP / ATP, and MtDNA analysis (see, e.g., Capela et al. Curr Res Toxicol. 2022;3:100075; Hubens et al. Mitochondrion. 2022;62:187-204; Taghizadeh et al., Free Radic. Biol. Med. 2016;99: 11-19).

[0460]

[0287] A reduction in neurotoxicity can be determined by measuring the change in a neurotoxicity biomarker in a subject before and after administration of the complex and / or comparator. Neurotoxicity biomarkers and methods for their measurement are known to those of skill in the art, and include, e.g., indicators of oxidative stress and dopamine-derived quinones, markers of mitochondrial dysfunction, and measures of glial cell activation (see, e.g., Taghizadeh et al., Free Radic. Biol. Med.

[0461] 2016;99:11-19). Glial activation may be assessed using established immunohistochemical or immunofluorescent approaches, including GFAP staining for reactive astrocytes and CD11 b staining for activated microglia (see, e.g., Herndon et al., Toxicol. Sci. 2014;138:130-138; Frau et al., J Neurochem. 2025-12-15 2013;124:69-78; Frau et al., Neurotoxicology. 2016;56:127-138). A reduction in neurotoxicity can also be determined by measuring the incidence or severity of serotonin syndrome in a subject.

[0462]

[0288] A reduction in cardiotoxicity can be determined by measuring the change in a cardiotoxicity biomarker in a subject before and after administration of the complex and / or comparator. Cardiotoxicity biomarkers and methods for their measurement are known to those of skill in the art, and include, e.g., measures of cardiac ion channel activity, cardiac conduction, arrhythmogenic risk, and cardiac rhythm abnormalities (e.g., irregular heartbeat, tachycardia).

[0463]

[0289] A reduction in renal toxicity can be determined by measuring the change in a renal toxicity biomarker in a subject before and after administration of the complex and / or comparator. Renal toxicity biomarkers and methods for their measurement are known to those of skill in the art, and include, e.g., rhabdomyolysis markers and / or kidney injury markers (e.g., muscular enzymes, creatinine phosphokinase).

[0464] b. Treatment of Mental, Behavioral, and Neurodevelopmental Disorders

[0290] Disclosed complexes may be useful for treating mental, behavioral, or neurodevelopmental disorders, and hence provided are methods of treating a mental, behavioral, or neurodevelopmental disorder in a subject, comprising administering a disclosed complex to a subject.

[0465]

[0291] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11. Although the terms “mental disorder” and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11, or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11, ICD-10, DSM-5, or DSM-IV (each of which is incorporated by reference herein in its entirety) whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.

[0466]

[0292] A mental, behavioral, or neurodevelopmental disorder where otherwise undefined, will be understood to refer to the disorder as defined in the ICD-11. Within the category of mental, behavioral, or neurodevelopmental disorders, the term mental disorder (or “mental health disorder”) generally refers to a disease condition that involves negative changes in emotion, mood, thinking, and / or behavior. In general, mental health disorders are characterized by clinically significant disturbances in an individual's cognition, emotion, behavior, or a combination thereof, resulting in impaired functioning, distress, or increased risk of suffering. Although the terms “mental disorder” and “mental health disorder,” as well as terms that define specific diseases and disorders, generally shall refer to the criteria in the ICD-11, or a patient with a diagnosis based thereon, it will be appreciated that disclosed methods are equally applicable to patients having an equivalent underlying disorder, whether that disorder is diagnosed based on the criteria in ICD-11, ICD-10, DSM-5, or DSM-IV (each of which is incorporated by reference herein in its entirety) 2025-12-15 whether the diagnosis is based on other clinically acceptable criteria, or whether the patient has not yet had a formal clinical diagnosis.

[0467]

[0293] In embodiments, disclosed complexes are used to treat a mental health disorder. In embodiments, disclosed complexes are administered, such as in a therapeutically effective amount, to a subject having a mental health disorder, thereby treating said mental health disorder. In some methods herein, the disclosed compositions, when administered in a therapeutically effective amount, provide beneficial therapeutic effects for the treatment of a mental health disorder. In embodiments, the complexes and compositions of the disclosure are used to reduce the symptoms of a mental health disorder. The symptoms of the mental health disorder to be treated shall be able to be determined by one of skill in the art, by reference to the general understanding of the art regarding that disorder.

[0468]

[0294] In embodiments, measures of therapeutic efficacy include reports by a subject or an observer. In embodiments, measures of therapeutic efficacy include responses to a questionnaire. Non-limiting representative examples of applicable measures of symptom improvement include the Generalized Anxiety Disorder Scale-7 (GAD-7), Montgomery-Asberg Depression Rating Scale (MADRS), Global Assessment of Functioning (GAF) Scale, Clinical Global Impression (CGI), Substance Abuse Questionnaire (SAQ), Mini International Neuropsychiatric Interview 5 (MINI 5), Columbia Suicide Severity Rating Scale (C-SSRS), Patient Health Questionnaire (PHQ-9), Pittsburgh Sleep Quality Index (PSQI), Interpersonal Reactivity Index (IRI), Short Form (36) Health Survey (SF-36), Self-Compassion Scale (SCS), Trauma History Questionnaire (THQ), Beck Depression Index (BDI), and related subject- or observer-reported measures.

[0469]

[0295] In embodiments, a disclosed complex is used to treat a mood disorder. The diagnosis of a mood disorder and determining that a subject is at risk of a mood disorder will be known to those in the art. Examples of mood disorders treatable using the disclosed complexes include depressive episodes, manic episodes, mixed episodes, and hypomanic episodes. In embodiments, the mood disorder is a bipolar or related disorder (e.g., bipolar type I disorder, bipolar type II disorder, cyclothymic disorder), a depressive disorder, or a substance-induced mood disorder. In embodiments, the mood disorder is a depressive disorder. As will be known to those of skill, depression can be assessed through the Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Depression Rating Scale, Beck Depression Inventory (BDI-II), Hamilton Rating Scale for Depression (HRSD), and other like tools.

[0470]

[0296] In embodiments, a disclosed complex is used to treat an anxiety or fear-related disorder. In embodiments, a subject has an anxiety or fear-related disorder. In embodiments, a subject is at risk of an anxiety or fear-related disorder. The diagnosis of an anxiety or fear-related disorder and determining that a subject is at risk of an anxiety or fear-related disorder will be known to those in the art. Examples of anxiety or fear-related disorders treatable using the disclosed complexes include generalized anxiety 2025-12-15 disorder, panic disorder, agoraphobia, specific phobia, social anxiety disorder, separation anxiety disorder, selective mutism, or a substance-induced anxiety disorder.

[0471]

[0297] In embodiments, a disclosed complex is used to treat an obsessive-compulsive or related disorder. In embodiments, a subject has an obsessive-compulsive or related disorder. In embodiments, a subject is at risk of an obsessive-compulsive or related disorder. The diagnosis of an obsessive-compulsive or related disorder and determining that a subject is at risk of obsessive-compulsive or related disorder will be known to those in the art. Examples of obsessive-compulsive or related disorders treatable using the disclosed complexes, include an obsessive-compulsive disorder, body dysmorphic disorder, olfactory reference disorder, hypochondriasis, hoarding disorder, a body-focused repetitive behavior disorder, or a substance-induced obsessive-compulsive disorder.

[0472]

[0298] In embodiments, a disclosed complex is used to treat a disorder associated with stress. In embodiments, a subject has a disorder associated with stress. In embodiments, a subject is at risk of a disorder associated with stress. The diagnosis of a disorder associated with stress and determining that a subject is at risk of a disorder associated with stress will be known to those in the art. In embodiments, the disorder associated with stress has an identifiable stressor that is a causal factor, like exposure to a stressful or traumatic event, or a series of such events or adverse experiences. Examples of disorders associated with stress treatable using the disclosed complexes include post-traumatic stress disorder, complex post-traumatic stress disorder, prolonged grief disorder, adjustment disorder, reactive attachment disorder, or disinhibited social engagement disorder.

[0473]

[0299] In embodiments, a disclosed complex is used to treat a disorder due to substance use or addictive behaviors. The diagnosis of a disorder due to substance use or addictive behaviors and determining that a subject is at risk of a disorder due to substance use or addictive behaviors will be known to those in the art. In embodiments, a disclosed complex is used to treat disorders due to substance use (i.e., a substance use disorder, or SUD). Examples of substance use disorders treatable using the disclosed complexes include alcohol use disorder (e.g., alcohol abuse, alcohol dependence, alcoholism), nicotine use disorder, cannabis use disorder, caffeine use disorder, phencyclidine use disorder, inhalants use disorder, opioids use disorder, sedatives use disorder, hypnotics use disorder, anxiolytics use disorder, stimulants use disorder, and tobacco use disorder. In embodiments, the substance use disorder is alcohol use disorder. In embodiments, the disorder is associated with another addictive behavior (e.g., gambling disorders, gaming disorder). In embodiments, a substance use disorder can be screened using a Screening to Brief Intervention (S2BI), Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST), Brief Screener for Alcohol, Tobacco, and other Drugs (BSTAD), Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS), the Opioid Risk Tool - OLID (ORT-OUD) Chart, Drug Abuse Screen Test (DAST-10), and Tobacco, Alcohol, Prescription medication, and other Substance use (TAPS). 2025-12-15

[0300] In embodiments, a disclosed complex is used to treat a personality disorder. The diagnosis of a personality disorder and determining that a subject is at risk of a personality disorder will be known to those in the art. Examples of personality disorders treatable using the disclosed complexes include antisocial personality disorder, avoidant personality disorder, borderline personality disorder, dependent personality disorder, histrionic personality disorder, masochistic or sadistic behavior, narcissistic personality disorder, obsessive-compulsive personality disorder, paranoid personality disorder, psychopathy, sociopathy, schizoid personality disorder, or schizotypal personality disorder.

[0474] c. Use in Psychotherapy

[0475]

[0301] In embodiments, administration of a disclosed complex to a subject produces a psychoactive effect in the subject. Accordingly, certain disclosed complexes may be useful as adjunctive therapeutics for psychotherapy. Hence, provided are methods of providing psychotherapy to a subject, comprising administering a disclosed complex to a subject in conjunction with or as an adjunct to psychotherapy.

[0476]

[0302] Herein, “psychoactive” effects may be used interchangeably with “psychedelic,” “empathogenic,” and “entactogenic” effects. Psychoactive effects can be assessed using one or more of a Peak Experience Scale (PES), e.g., as described in Reckweg et al., Front Pharmacol. 2021; 12:760671, the Mystical Experience Questionnaire (MEQ), the Ego Dissolution Inventory (EDI), the Challenging Experience Questionnaire (CEQ), and the 5-Dimensional Altered States of Consciousness Questionnaire (5D-ASC). In embodiments, onset and duration of psychoactive effects may be determined by observing and / or interviewing the subject, such as by using a self-report symptom questionnaire, or by asking the subject to document subjective psychoactive effects, i.e., the subject’s experience. In embodiments, the self-report symptom questionnaire is the Subjective Drug Effects Questionnaire (SDEQ), a 272-item questionnaire measuring perceptual, mood, and somatic changes caused by psychedelics (Katz et al. J Abnorm Psych, 1968;73:1-14). In embodiments, the self-report symptom questionnaire is the List of Complaints (LC), a 66-item questionnaire that reliably measures physical and general discomfort (see, e.g., Holze et al. 2022. Psychopharmacol, 239:1893-1905). Psychoactive effects and onset and duration of such effects may additionally be determined according to methods known to one of skill in the art.

[0477]

[0303] Examples of psychotherapy, such as psychosocial or behavioral therapy, that may be administered to a subject in conjunction with a disclosed complex include cognitive behavioral therapy (e.g., as described in Arch Gen Psychiatry 1999; 56:493-502), interpersonal therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174), contingency management based therapy (e.g., as described in Psychol Addict Behav 2009; 23(1): 168-174; in J Consul Clin Psychol 2005; 73(2): 354-59; or in Case Reports in Psychiatry, Vol. 2012, Article ID 731638), motivational interviewing based therapy (e.g., as described in J Consul Clin Psychol 2001; 69(5): 858-62), meditation based therapy, such as transcendental meditation based therapy (e.g., as described in J Consul Clin Psychol 2000; 68(3): 515-52), or the 2025-12-15 therapeutic approach used by MAPS to treat patients with PTSD (e.g., as in Mithoefer, M (2017). Manual for MDMA-Assisted Psychotherapy in the Treatment of Post-traumatic Stress Disorder).

[0478]

[0304] In embodiments, “psychotherapy” is specifically “psychedelic-assisted psychotherapy.” Psychedelic-assisted psychotherapy, broadly, includes a range of related approaches that involve at least one session where the patient ingests a psychedelic and is monitored, supported, or otherwise engaged by one or more trained mental health professionals while under the effects of the psychedelic (see, e.g., Schenberg 2018). Protocols have been developed for the standardization of procedures which emphasize a high degree of care (see, e.g., Johnson 2008), such as the therapeutic approach used by MAPS to treat patients with PTSD using MDMA (e.g., as described in Mithoefer 2017).

[0479]

[0305] In embodiments, the psychotherapy conducted with a disclosed complex is conducted in widely spaced sessions. These sessions can be as frequently as weekly but are more often approximately monthly or less frequently. In most cases, a small number of sessions, on the order of one to three, is needed for a patient to experience significant clinical progress, as indicated, for example, by a reduction in the symptoms of the mental health disorder being treated. In embodiments, psychotherapy comprises multiple sessions, during some of which a disclosed complex is administered (“drug-assisted psychotherapy”); in others, the patient participates in psychosocial or behavioral therapy without concomitant administration of a drug, or without administration of a disclosed complex.

[0480] G. Exemplary Aspects and Embodiments

[0481]

[0306] The following aspects and embodiments are included for illustrative purposes only and are not intended to limit the scope of the invention. These aspects and embodiments are not an extensive overview of the invention. They are not intended to identify key or critical elements of the invention or to delineate the scope thereof.

[0482]

[0307] In one aspect, provided is a metal-drug coordination complex comprising:

[0483] a. a pharmacologically active agent having the structure of Formula (I),

[0484]

[0485] wherein L is H or a ligand moiety; and

[0486] b. a metal ion;

[0487] wherein the pharmacologically active agent is coordinated to the metal ion.

[0488]

[0308] In embodiments, the complex is four-coordinate complex. In embodiments, the complex has square planar geometry. In embodiments, the complex has tetrahedral geometry.

[0489]

[0309] In embodiments, the complex is a five-coordinate complex. In embodiments, the complex has square pyramidal geometry. In embodiments, the complex has trigonal bipyramidal geometry. 2025-12-15

[0310] In embodiments, the complex is a six-coordinate complex. In embodiments, the complex has octahedral geometry.

[0490]

[0311] In embodiments, L is H.

[0491]

[0312] In embodiments, the complex has the structure of Formula (M4),

[0492] . IVT

[0493] X

[0494]

[0495] (M4),

[0496] wherein RNis H or absent, and each X is independently a coordinating solvent molecule, a coordinating anion, or a coordinating atom from an additional molecule of the pharmacologically active agent.

[0497]

[0313] In embodiments, the complex has the structure of Formula (M5),

[0498]

[0499] wherein RNis H or absent, and each X is independently a coordinating solvent molecule, a coordinating anion, or a coordinating atom from an additional molecule of the pharmacologically active agent.

[0500]

[0314] In embodiments, the complex has the structure of Formula (M6),

[0501]

[0502] wherein RNis H or absent, and each X is independently a coordinating solvent molecule, a coordinating anion, or a coordinating atom from an additional molecule of the pharmacologically active agent.

[0503]

[0315] In embodiments, wherein L is a ligand moiety. In embodiments, the ligand moiety is an amino acid moiety.

[0504]

[0316] In embodiments, the pharmacologically active agent has the structure of

[0505] O

[0506]

[0507] , wherein R is an amino acid side chain, H, unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6thioalkyl, C1-C6aminoalkyl, or C1-C6alkyl substituted by aryl, heteroaryl, oxo, carboxylate, or amido; and R' is H or — COCH3.

[0508]

[0317] In embodiments, R' is H. In embodiments, R' is — COCH3. 2025-12-15

[0318] In embodiments, the complex has the structure of Formula (A4a) or (A4b):

[0509]

[0510] (A4a), wherein RNis H or absent, and each X is independently a coordinating solvent molecule, a coordinating anion, or a coordinating atom from an additional molecule of the pharmacologically active agent.

[0511]

[0319] In embodiments, the complex has the structure of Formula (A5a) or (A5b):

[0512]

[0513] wherein RNis H or absent, and each X is independently a coordinating solvent molecule, a coordinating anion, or a coordinating atom from an additional molecule of the pharmacologically active agent.

[0514]

[0320] In embodiments, the complex has the structure of Formula (A6a) or (A6b):

[0515]

[0516] wherein RNis H or absent, and each X is independently a coordinating solvent molecule, a coordinating anion, or a coordinating atom from an additional molecule of the pharmacologically active agent.

[0517]

[0321] In embodiments, R is an amino acid side chain. In embodiments, R is H, unsubstituted C1-C6alkyl, C1-C6hydroxyalkyl, C1-C6thioalkyl, C1-C6aminoalkyl, or C1-C6alkyl substituted by aryl, heteroaryl, oxo, carboxylate, or amido.

[0518]

[0322] In embodiments, the metal ion is a transition metal ion. In embodiments, the transition metal ion is a zinc ion, silver ion, cobalt ion, copper ion, nickel ion, iron ion, manganese ion, gold ion, or palladium ion.

[0519]

[0323] In another aspect, provided is a metal-drug coordination complex having the structure of: 2025-12-15

[0520]

[0521] wherein RNis H or absent, and M is Zn2+, Ag+, Co2+, Co3+, Cu+, Cu2+, Ni2+, Fe2+, Fe3+, Mn2+, Mn3+, Mn4+, Au+, or Pd2+.

[0522]

[0324] In another aspect, provided is a metal-drug coordination complex having the structure of:

[0523]

[0524] wherein RNis H or absent, and M is Zn2+, Ag+, Co2+, Co3+, Cu+, Cu2+, Ni2+, Fe2+, Fe3+, Mn2+, Mn3+, Mn4+, Au+, or Pd2+.

[0525]

[0325] In another aspect, provided is a metal-drug coordination complex having the structure of:

[0526]

[0527] wherein RNis H or absent; M is Zn2+, Ag+, Co2+, Co3+, Cu+, Cu2+, Ni2+, Fe2+, Fe3+, Mn2+, Mn3+, Mn4+, Au+, or Pd2+; and each X is independently a coordinating solvent molecule, a coordinating anion. In embodiments, X is H2O.

[0528]

[0326] In embodiments, the transition metal ion is Zn2+, Ag+, Co2+, Co3+, Cu+, Cu2+, Ni2+, Fe2+, Fe3+, Mn2+, Mn3+, Mn4+, Au+, or Pd2+. In embodiments, M is Fe2+or Fe3+. In embodiments, M is Zn2+. In embodiments, M is Mn2+, Mn3+, or Mn4+. In embodiments, M is Ni2+.

[0529]

[0327] In another aspect, provided is a pharmaceutical composition comprising a therapeutically effective amount of the complex of any of the disclosed embodiments, and a pharmaceutically acceptable carrier, diluent, or excipient. In embodiments, the composition is suitable for oral, buccal, sublingual, intranasal, injectable, subcutaneous, intravenous, intraocular, topical, or transdermal administration. In 2025-12-15 embodiments, the composition is in unit dosage form. In embodiments, the composition comprises the complex in a total amount of between about 0.01 and 100 mg.

[0530]

[0328] In embodiments, the composition further comprises a therapeutically effective amount of an additional active compound, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof. In embodiments, the additional active compound is selected from the group consisting of amino acids, antioxidants, anti-inflammatory agents, analgesics, antineuropathic and antinociceptive agents, antimigraine agents, anxiolytics, antidepressants, antipsychotics, anti-PTSD agents, dissociatives, cannabinoids, immunostimulants, anti-cancer agents, antiemetics, orexigenics, antiulcer agents, antihistamines, antihypertensives, anticonvulsants, antiepileptics, bronchodilators, neuroprotectants, nootropics, empathogens, psychedelics, plasticity-inducing agents, monoamine oxidase inhibitors, tryptamines, terpenes, phenethylamines, sedatives, stimulants, serotonergic agents, NMDA modulators, NMDA antagonists, and vitamins.

[0531]

[0329] In another aspect, provided is a method of modulating neurotransmission in a subject, comprising administering to the subject the complex or composition of any of the disclosed embodiments. In embodiments, the neurotransmission is one or more of serotonergic neurotransmission, dopaminergic neurotransmission, and noradrenergic neurotransmission.

[0532]

[0330] In another aspect, provided is a method of increasing neuroplasticity in a subject, comprising administering to the subject the complex or composition of any of the disclosed embodiments.

[0533]

[0331] In another aspect, provided is a method of treating a medical condition in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of the complex or composition of any of the disclosed embodiments.

[0534]

[0332] In embodiments, the medical condition is a disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission, dopaminergic neurotransmission, or noradrenergic neurotransmission.

[0535]

[0333] In embodiments, the medical condition is a mental, behavioral, or neurodevelopmental disorder. In embodiments, the medical condition is a neurodevelopmental disorder, schizophrenia or another primary psychotic disorder, catatonia, a mood disorder, an anxiety or fear-related disorders, an obsessive-compulsive or related disorder, a disorder specifically associated with stress, a dissociative disorder, a feeding or eating disorder, an elimination disorder, a disorder of bodily distress or bodily experience, a disorder due to substance use or addictive behavior, an impulse control disorder, a disruptive behavior or dissocial disorder, a personality disorder, a paraphilic disorder, a factitious disorder, a neurocognitive disorder, a mental or behavioral disorder associated with pregnancy, childbirth or the puerperium, a sleep-wake disorder, or a sexual dysfunction.

[0536]

[0334] In embodiments, the complex is administered together with one or more sessions of psychotherapy. 2025-12-15 H. Examples

[0537]

[0335] The following examples are included for illustrative purposes only and are not intended to limit the scope of the invention.

[0538] Example 1: Preparation of 2-amino-N-[1-(1,3-benzodioxol-5-yl)propan-2-yl]-N,3-dimethyl butanamide (MDMA-Val);

[0539]

[0540]

[0336] In an oven-dried 10 mL Schlenk flask under an N2atmosphere, 3,4-methylenedioxymethamphetamine (MDMA) hydrochloride (0.193 g, 0.840 mmol) was dissolved in anhydrous tetrahydrofuran (4 mL). The flask was capped with a rubber septum. N, N-diisopropylethylamine (DIPEA) (0.22 mL, 1.26 mmol) was added by syringe and the resulting clear, colorless solution was magnetically stirred at room temperature. Boc-L-valine hydroxysuccinimide ester (0.314 g, 1.00 mmol) was added in one portion under N2flush. The reaction was stirred at ambient temperature (~22 °C) for 24 hours, after which the reaction was quenched by the addition of deionized water (1 mL). The solvents were removed by rotary evaporation to yield an off-white solid. The solid was redissolved in ethyl acetate (10 mL), and this solution was washed with saturated aqueous NaHCO3(3 x 20 mL) and brine (1 x 20 mL). The ethyl acetate solution was dried over anhydrous MgSO4, filtered, and evaporated to dryness to yield the product, 2-amino-N-[1-(1,3-benzodioxol-5-yl)propan-2-yl]-N,3-dimethyl butanamide (MDMA-Val) as a tacky, white solid (0.117 g, 4.0 mmol, 48% yield). The product was characterized by nuclear magnetic resonance and mass spectrometry; characterization data matched those previously reported (see WO 2023 / 283373).

[0541] Example 2: Preparation and Characterization of [M][MDMA-Val] Complexes

[0542]

[0337] Purpose: This example demonstrates the preparation of exemplary metal-drug coordination complexes comprising an MDMA-Val active agent, and the characterization of the complexes by mass spectrometry (MS) and color change.

[0543]

[0338] Methods: A clear, colorless solution of zinc nitrate (10 mg, 0.053 mmol) in acetonitrile (2 mL) was added to a solution of MDMA-Val (30.9 mg, 0.11 mmol) in acetonitrile (2 mL). The resulting solution was stirred for 30 minutes at 20 °C. Evaporation of the acetonitrile produced [Zn(MDMA-Val)2(H2O)2] as a clear, colorless gel. MS (+ESI) (CH3CN): m / z 683.25 [Zn(C16H23N2O3)2(H2O)2(H)]+calc. 683.30.

[0544]

[0339] A yellow solution of iron(lll) chloride hexahydrate (10 mg, 0.037 mmol) in acetonitrile (2 mL) was added to a solution of MDMA-Val (21.6 mg, 0.07 mmol) in acetonitrile (2 mL). The resulting solution turned brown and was stirred for 30 minutes at 20 °C. Evaporation of the acetonitrile produced [Fe(MDMA-Val)2(H2O)2] as a yellowish gel. MS (+ESI) (CH3CN): m / z 675.26 [Fe(C16H23N2O3)2(H2O)2(H)]+calc. 675.31. 2025-12-15

[0340] A faintly pink solution of manganese(ll) nitrate tetrahydrate (10 mg, 0.034 mmol) in acetonitrile (2 mL) was added to a solution of MDMA-Val (20.1 mg, 0.069 mmol) in acetonitrile (2 mL). The resulting solution turned faint yellow and was stirred for 30 minutes at 20 °C. Evaporation of the acetonitrile produced [Mn(MDMA-Val)2(H2O)2] as a yellowish gel. MS (+ESI) (CH3CN): m / z 674.26 [Mn(C16H23N2O3)2(H2O)2(H)]+calc. 674.31.

[0545]

[0341] A deep blue solution of nickel(ll) nitrate hexahydrate (10 mg, 0.040 mmol) in acetonitrile (2 mL) was added to a solution of MDMA-Val (23.3 mg, 0.08 mmol) in acetonitrile (2 mL). The resulting solution turned bottle green and was stirred for 30 minutes at 20 °C. Evaporation of the acetonitrile produced [Ni(MDMA-Val)2(H2O)2] as a bottle green gel. MS (+ESI) (CH3CN): m / z 321.14 [Ni(C16H24N2O3)2]2+calc. 321.15.

[0546]

[0342] A deep blue solution of copper(ll) nitrate trihydrate (10 mg, 0.041 mmol) in acetonitrile (2 mL) was added to a solution of MDMA-Val (24.2 mg, 0.083 mmol) in acetonitrile (2 mL). The resulting solution turned lime green and was stirred for 30 minutes at 20 °C. Evaporation of the acetonitrile produced [Cu(MDMA-Val)2(H2O)2] as a lime green gel. MS (+ESI) (CH3CN): m / z 704.28 [Cu(C16H24N2O3)2(H2O)2][Na]+calc. 704.28.

[0547]

[0343] Exact amounts of reactants and solvents used for each reaction are listed below:

[0548] Metal salt Product complex formula Complex mass Product mlz Metal salt Complex color color indicated by ESI-MS (calculated) by ESI-MS [Zn(H2O)6](NO3)2colorless [Zn(MDMA-Val)2(H2O)2].683.30 683.25 colorless [Fe(H2O)6]Cl3yellow [Fe(MDMA-Val)2(H2O)2] 675.31 675.26 yellow [Mn(H2O)4](NO3)2faint pink [Mn(MDMA-Val)2(H2O)2] 674.31 674.26 yellow Ni(H2O)6(NO3)2deep blue [Ni(MDMA-Val)2] 321.15 321.14 bottle green Cu(H2O)3(NO3)2deep blue [Cu(MDMA-Val)2(H2O)2] 704.28 704.28 lime green

[0549]

[0550]

[0344] The MDMA-Val starting material and the complexes were characterized by mass spectrometry (MS) (FIGS. 1-6) High resolution accurate mass samples were analysed on a Synapt XS (Waters Corporation, MA, USA) coupled to a Acquity Premier UPLC (Waters Corporation, MA, USA). 0.5 uL sample was injected into a flow of 50:50 water(0.5% formic acid):acetonitrile at 0.2 mL / min. Leucine Enkephalin was injected as Lock Mass. The data was acquired using MassLynx software (Waters Corporation) and processed using WatersConnect and UNIFI.

[0551]

[0345] Results: Results indicated the formation of stable complexes, as also evidenced by the isolation of a new solid or gel-phase material with properties distinct from the physical properties of the starting materials. MS analysis provided spectrometric evidence for the formation of the complexes.

[0552]

[0346] For reference, FIG. 1 shows the MS analysis for MDMA-Val (C16H24N2O3). Exact mass = 293.19; observed m / z = 293.19 (100.0%), 294.18 (18.4%), 295.19 (1.5%). FIGS. 2-6 show the MS analysis for the synthesized complexes. 2025-12-15

[0347] The MS data indicate the formation of the expected complexes, which can be distinguished from unreacted starting materials or side products by characteristic m / z peaks corresponding to calculated complex masses.

[0553]

[0348] The complexes exhibited properties consistent with coordination of the MDMA-AA active agent to the metal center, such as changes in color that are characteristic to complexes of Zn(ll), Fe(lll), Mn(ll), Ni(ll), and Cu(ll).

[0554] Example 3: Active Agent Release in Serum

[0555]

[0349] Pooled mixed gender human plasma (2 mL), mouse plasma, rat plasma and dog plasma are equilibrated at 37 °C. A disclosed complex is added so as to achieve a concentration of 1.0 pg / mL. Aliquots (50 pL) of the mixture are withdrawn at timed intervals (e.g., at 0 min, 0.5 min, 1 min, 5 min, 10 min, 30 min, 1 h, 2 h, and 4h) and quenched with 200 pL of methanol / acetonitrile (1:1). The samples are vortexed and stored at -80° C until analysis. Assays are done in triplicate. Control samples are done in phosphate buffered saline (PBS, pH 7.4) and simulated gastric fluid (SGF, pH 2). Analysis of samples is performed by HPLC-MS to determine the amounts of complex and active agent in each sample tested. The mean concentrations remaining at different time points of the experiment are determined.

[0556]

[0350] Differences in release kinetics between complexes comprising different metals and / or amino acid ligand moieties may demonstrate that metal-ligand coordination strength, ligand denticity, and other design parameters can be used to tune release kinetics.

[0557] Example 4: Absorption and Hydrolysis in an In Vitro Model of Human Intestinal Mucosa

[0351] Purpose: Caco-2 cells are derived from the human colon adenocarcinoma cell line, and are a valuable in vitro model for studying drug absorption in intestinal cells. In this assay, Caco-2 cells are cultured on transwell inserts with a semi-porous polycarbonate membrane, forming a continuous monolayer that closely mimics the morphology and function of human small intestinal epithelial cells, and compartments on either side to mimic the intestinal lumen and bloodstream. With marker enzyme expression, uptake, transport, and permeability characteristics akin to those of small intestinal epithelial cells, Caco-2 cells offer a robust model for understanding drug absorption processes. Research suggests in vitro cell experiments using Caco-2 cells can provide more accurate insights into drug absorption compared to animal experiments (Truffin et al. Future Pharmacol. 2023;3(1):229-237; Liu et al. Food Funct.

[0558] 2020; 11(5):4014-4025).

[0559]

[0352] Methods: A Caco-2 permeability assay is performed using the CacoReady™ model (Readycell, Barcelona, Spain) consisting of Caco-2 cells seeded on polycarbonate filters (0.4 pm pore size, 6.5 mm diameter), in the apical chamber of 24-well high throughput screening plates (Corning Incorporated, NY, USA). Cells are seeded at a density of 1 x 105cells per mL in an appropriate medium and buffer solution. Cell culturing proceeds at 37 °C for 21 days, with culture medium changes every 2025-12-15 second day to allow the formation of a confluent monolayer. The apical chamber represents the intestinal lumen, and the basal chamber represents the bloodstream.

[0560]

[0353] Prior to experimentation, the integrity of the monolayer is assessed by measuring the transepithelial electrical epithelial resistance (TEER), and the apparent permeability coefficient (Papp) of the monolayer is assessed by measuring the permeability of a fluorescent paracellular marker. Only wells with a TEER value >600 Q cm-2and Papp<0.8 x 10“6cm s“1are used in the transport experiments.

[0561]

[0354] The culture media in the apical and basal chambers are removed and washed with the pre-warmed buffer solution (at 37 °C 15 min in an incubator) twice. 1.25 mL of prewarmed buffer is added in the basal chamber. Test complexes are dissolved in DMSO and properly diluted in buffer to obtain a final DMSO concentration of 0.1% (v / v). 0.25 mL of the test complex solution is then added into the apical chamber of the transwells. 0.5 mL aliquots of solution are taken from the basal chamber of the trans-wells at 0.5, 1, 2, and 4 h intervals. The concentrations of a test complex, active agent, and any hydrolyzed metabolites in these samples are determined by HPLC. An equal volume of buffer solution is added to the transwells after taking a sample to compensate for the reduction in total volume. The TEER value of the monolayer is monitored throughout the whole experiment.

[0562]

[0355] Results & Significance: Results can show that certain disclosed complexes are likely to be absorbed and hydrolyzed by human intestinal mucosa cells. The absorption and hydrolysis rate is also evaluated and compared amongst complexes. Results can be represented as a concentration (pg / mL) per incubation time. Differences between the in vitro absorption and hydrolysis of disclosed complexes and suitable comparators (e.g., MDMA) are also determined according to the described methods.

[0563] Example 5: In Vivo Pharmacokinetics of Disclosed Complexes in Rats

[0564]

[0356] Disclosed complexes are administered to rats by injection (intravenous and subcutaneous) with a sterile solution (2 mg / mL) at a rate of 1.4-2 mg / kg. Blood samples are taken at 15, 30, 45, 60, 120, 240 min and 360 min and analyzed by LC-MS for the disclosed complex (i.e., the prodrug) and its corresponding component active agent (and any hydrolyzed metabolites thereof). The pharmacokinetic (PK) profile for the complex and active agent(s) are obtained and relative bioavailability is determined for each of the routes of administration. PK-PD type curves can be generated to demonstrate the activity of disclosed complexes. PK parameters that can be determined according to this assay include Cmax, Tmax, t1 / 2, AUC, and bioavailability.

[0565]

[0357] A complex may exhibit reduced Cmaxand / or increased Tmaxrelative to the corresponding free constituent active agent, consistent with controlled release and altered tissue distribution.

[0566] Example 6: In Vitro Metabolic Stability

[0567]

[0358] Purpose: The purpose of this experiment is to assess the metabolic stability of disclosed complexes in an in vitro assay. See, e.g., Ackley et al., Metabolic Stability Assessed by Liver Microsomes 2025-12-15 and Hepatocytes. In Yan & Caldwell (eds) Optimization in Drug Discovery. Methods Pharmacol Toxicol. Humana Press, and Richardson et al., Drug Metab Lett. 2016; 10(2):83-90).

[0568]

[0359] Methods: A liver microsomal stability assay is performed according to available methods, e.g., in accordance with the methods described in US 2008 / 0045588 with modifications. Briefly, the assay is conducted at 1 mg / mL liver microsome protein with an NADPH-generating system in 2% NaHCO3 (2.2 mM NADPH, 25.6 mM glucose 6-phosphate, 6 units per mL glucose 6-phosphate dehydrogenase and 3.3 mM MgCI2). Test complexes are prepared as solutions in 20% acetonitrile-water and added to the assay mixture (final assay concentration 5 microgram per mL) and incubated at 37° C. Aliquots (50 pL) are removed at times 0, 15, 30, 45, and 60 min, and diluted with ice cold acetonitrile (200 pL) to stop the reactions. Samples are centrifuged at 12,000 rpm for 10 min to precipitate proteins. Supernatants are transferred to microcentrifuge tubes and stored for LC / MS / MS analysis of the degradation half-life of the test complexes.

[0569]

[0360] Results & Significance: Results will show a measurement of the in vitro intrinsic clearance of disclosed complexes. Such data provides a prediction of the metabolic stability and clearance of the complexes.

[0570] Example 7: Reduced Adverse Effects of an MDMA-Metal Complex

[0571]

[0361] Purpose: The purpose of this experiment is to compare the adverse side effects of MDMA and a disclosed complex in humans. MDMA has a variety of side effects including inflammation, immunosuppression, oxidative stress, and mitochondrial dysfunction. These side effects may be ameliorated by targeted delivery of antioxidant / antiinflammatory substances to the sites of MDMA action, such as the metal core (e.g., Zn(ll)) of disclosed complexes.

[0572]

[0362] Methods: Forty participants are enrolled into a randomized, double-blind trial to compare the adverse effects of MDMA and a disclosed complex. Participants will receive one of two treatments: a standard therapeutic dose of MDMA (e.g., 120 mg) (MDMA group) or an equivalent dose of an MDMA-metal complex (MDMA-metal complex group). Blood samples will be collected prior to administration, 2 hours, 6 hours, and 24 hours post-administration. Blood samples will be centrifuged to separate the plasma and cell fraction, and stored at -80° C until biomarker analysis.

[0573]

[0363] An adverse effect biomarker panel analysis is run on the blood samples to assess the adverse effects of each treatment. The biomarker panel includes analysis of inflammation response biomarkers (e.g., IL-ip, IL-6, IL-12, and TNF-a), immunity biomarkers (e.g., CD4+T cells, T cell proliferation, and circulating NK cells), oxidative stress biomarkers (e.g., malondialdehyde and 8-OHdG), and mitochondrial dysfunction biomarkers (e.g., ATP level, mitochondrial membrane potential, MtDNA analysis). Biomarker levels are assessed with a combination of Enzyme-Linked Immunosorbent Assay (ELISA) or other dye reaction assays where appropriate (e.g., thiobarbituric acid reactive substances (TBARS) assay to detect malondialdehyde). 2025-12-15

[0364] Results & Significance: The biomarker panel of the MDMA-metal complex group will have significantly lower inflammation response biomarker levels, high immunity biomarker levels, lower oxidative stress biomarker levels, and lower mitochondrial dysfunction biomarker levels than the MDMA group. In embodiments, complexes comprising zinc exhibit greater reductions in oxidative stress biomarkers relative to complexes comprising other metals.

[0574]

[0365] The foregoing description, for purposes of explanation, uses specific nomenclature to provide a thorough understanding of the invention. However, it will be apparent to one skilled in the art that specific details are not required in order to practice the invention. Thus, the foregoing description of specific embodiments of the invention is presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise compositions, formulations, methods, or the like disclosed; many modifications and variations are possible in view of the above teachings. The embodiments were chosen and described in order to best explain the principles of the invention and its practical applications, through the elucidation of specific examples, and to thereby enable others skilled in the art to best utilize the invention and various embodiments with various modifications as are suited to the particular use contemplated, when such uses are beyond the specific examples disclosed. Accordingly, the scope of the invention shall be defined solely by the following claims and their equivalents.

Claims

2025-12-15CLAIMSThe invention claimed is:

1. A metal-drug coordination complex comprising a metal coordinated to one or more pharmacologically active agents having the structure of Formula (I),wherein L is a ligand moiety or H; or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

2. The complex of claim 1, wherein L is a ligand moiety.

3. The complex of claim 2, wherein the ligand moiety comprises an amino acid.

4. The complex of claim 3, wherein the amino acid is alanine, arginine, asparagine, aspartic acid, cysteine, selenocysteine, / V-acetylcysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, or valine.

5. The complex of claim 3, wherein the amino acid is an (L)-isomer.

6. The complex of claim 3, wherein the amino acid is a (D)-isomer.

7. The complex of claim 3, wherein the one or more pharmacologically active agents have the structure of:wherein R is an amino acid side chain, and R' is H or— COCH3.

8. The complex of claim 7, wherein R' is H.

9. The complex of claim 7, wherein R' is — COCH3.

10. The complex of claim 7, wherein R is C1-C12alkyl, C1-C6hydroxyalkyl, C1-C6alkylthio, C1-C6aminoalkyl, C1-C6carboxyalkyl, C1-C6alkylene-C6-C12aryl, C1-C6alkylene— (3- to10-membered heteroaryl), C1-C6alkylene— guanidino, C1-C6alkylene-CONH2, or H; or R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl.

11. The complex of claim 10, wherein R is C1-C6alkyl.

12. The complex of claim 11, wherein R is isopropyl.

13. The complex of claim 11, wherein R is methyl.

14. The complex of claim 11, wherein R is sec-butyl.2025-12-15 15. The complex of claim 11, wherein R is isobutyl.

16. The complex of claim 10, wherein R is C1-C6hydroxyalkyl.

17. The complex of claim 16, wherein R is -CH2OH.

18. The complex of claim 10, wherein R is C1-C6thioalkyl.

19. The complex of claim 18, wherein R is -CH2SH.

20. The complex of claim 18, wherein R is -(CH2)2SCH3.

21. The complex of claim 10, wherein R is C1-C6aminoalkyl.

22. The complex of claim 21, wherein R is -(CH2)4NH2or -(CH2)4NH3+.

23. The complex of claim 10, wherein R is C1-C6carboxyalkyl.

24. The complex of claim 23, wherein R is -CH2COOH or -CH2COO’.

25. The complex of claim 23, wherein R is -(CH2)2COOH or -(CH2)2C00‘.

26. The complex of claim 10, wherein R is C1-C6alkylene-C6-C12aryl.

27. The complex of claim 26, wherein R is -CH2-phenyl.

28. The complex of claim 26, wherein R is -CH2-(4-hydroxyphenyl).

29. The complex of claim 10, wherein R is C1-C6alkylene–(3- to 10-membered heteroaryl).

30. The complex of claim 29, wherein R is –CH2–imidazol-4-yl.

31. The complex of claim 29, wherein R is –CH2–(3-indolyl).

32. The complex of claim 10, wherein R is C1-C6alkylene–guanidino.

33. The complex of claim 32, wherein R is –(CH2)3–guanidino.

34. The complex of claim 10, wherein R is C1-C6alkylene-CONH2.

35. The complex of claim 34, wherein R is -CH2CONH2or -CH2CONH2.

36. The complex of claim 34, wherein R is -(CH2)2CONH2or -(CH2)2CONH2.

37. The complex of claim 10, wherein R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl.

38. The complex of claim 37, wherein R and R' are taken together with the intervening atoms to form a pyrrolidinyl.

39. The complex of claim 10, wherein R is H.

40. The complex of claim 8, having the structure of:2025-12-15 wherein R is an amino acid side chain.

41. The complex of claim 40, wherein R is C1-C12alkyl, C1-C6hydroxyalkyl, C1-C6alkylthio, C1-C6aminoalkyl, C1-C6carboxyalkyl, C1-C6alkylene–C6-C12aryl, C1-C6alkylene–(3- to 10-membered heteroaryl), C1-C6alkylene–guanidino, C1-C6alkylene–CONH2, or H; or R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl.

42. The complex of claim 41, wherein R is C1-C6alkyl.

43. The complex of claim 42, wherein R is isopropyl.

44. The complex of claim 42, wherein R is methyl.

45. The complex of claim 42, wherein R is sec-butyl.

46. The complex of claim 42, wherein R is isobutyl.

47. The complex of claim 41, wherein R is C1-C6hydroxyalkyl.

48. The complex of claim 47, wherein R is -CH2OH.

49. The complex of claim 41, wherein R is C1-C6thioalkyl.

50. The complex of claim 49, wherein R is -CH2SH.

51. The complex of claim 49, wherein R is -(CH2)2SCH3.

52. The complex of claim 41, wherein R is C1-C6aminoalkyl.

53. The complex of claim 52, wherein R is -(CH2)4NH2or -(CH2)4NH3+.

54. The complex of claim 41, wherein R is C1-C6carboxyalkyl.

55. The complex of claim 54, wherein R is -CH2COOH or -CH2COO’.

56. The complex of claim 54, wherein R is -(CH2)2COOH or -(CH2)2COO’.

57. The complex of claim 41, wherein R is C1-C6alkylene-C6-C12aryl.

58. The complex of claim 57, wherein R is -CH2-phenyl.

59. The complex of claim 57, wherein R is -CH2-(4-hydroxyphenyl).

60. The complex of claim 41, wherein R is C1-C6alkylene–(3- to 10-membered heteroaryl).

61. The complex of claim 60, wherein R is –CH2–imidazol-4-yl.

62. The complex of claim 60, wherein R is –CH2–(3-indolyl).

63. The complex of claim 41, wherein R is C1-C6alkylene–guanidino.

64. The complex of claim 63, wherein R is –(CH2)3–guanidino.

65. The complex of claim 41, wherein R is C1-C6alkylene-CONH2.

66. The complex of claim 65, wherein R is -CH2CONH2or -CH2CONH2.

67. The complex of claim 65, wherein R is -(CH2)2CONH2or -(CH2)2CONH2.

68. The complex of claim 41, wherein R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl.

69. The complex of claim 68, wherein R and R' are taken together with the intervening atoms to form a pyrrolidinyl.2025-12-15 70. The complex of claim 41, wherein R is H.

71. The complex of claim 8, having the structure of:wherein R is an amino acid side chain and each X is independently a solvent molecule or a coordinating anion.

72. The complex of claim 71, wherein both of X are solvent molecules.

73. The complex of claim 72, wherein both of X are H2O.

74. The complex of claim 71, wherein R is C1-C12alkyl, C1-C6hydroxyalkyl, C1-C6alkylthio, C1-C6aminoalkyl, C1-C6carboxyalkyl, C1-C6alkylene–C6-C12aryl, C1-C6alkylene–(3- to 10-membered heteroaryl), C1-C6alkylene–guanidino, C1-C6alkylene–CONH2, or H; or R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl.

75. The complex of claim 74, wherein R is C1-C6alkyl.

76. The complex of claim 75, wherein R is isopropyl.

77. The complex of claim 75, wherein R is methyl.

78. The complex of claim 75, wherein R is sec-butyl.

79. The complex of claim 75, wherein R is isobutyl.

80. The complex of claim 74, wherein R is C1-C6hydroxyalkyl.

81. The complex of claim 80, wherein R is -CH2OH.

82. The complex of claim 74, wherein R is C1-C6thioalkyl.

83. The complex of claim 82, wherein R is -CH2SH.

84. The complex of claim 82, wherein R is -(CH2)2SCH3.

85. The complex of claim 74, wherein R is C1-C6aminoalkyl.

86. The complex of claim 85, wherein R is -(CH2)4NH2or -(CH2)4NH3+.

87. The complex of claim 74, wherein R is C1-C6carboxyalkyl.

88. The complex of claim 87, wherein R is -CH2COOH or -CH2COO’.

89. The complex of claim 87, wherein R is -(CH2)2COOH or -(CH2)2C00‘.

90. The complex of claim 74, wherein R is C1-C6alkylene-C6-C12aryl.

91. The complex of claim 90, wherein R is -CH2-phenyl.

92. The complex of claim 90, wherein R is -CH2-(4-hydroxyphenyl).

93. The complex of claim 74, wherein R is C1-C6alkylene— (3- to 10-membered heteroaryl).2025-12-15 94. The complex of claim 93, wherein R is –CH2–imidazol-4-yl.

95. The complex of claim 93, wherein R is –CH2–(3-indolyl).

96. The complex of claim 74, wherein R is C1-C6alkylene— guanidi no.

97. The complex of claim 96, wherein R is –(CH2)3–guanidino.

98. The complex of claim 74, wherein R is C1-C6alkylene-CONH2.

99. The complex of claim 98, wherein R is -CH2CONH2or -CH2CONH2.

100. The complex of claim 98, wherein R is -(CH2)2CONH2or -(CH2)2CONH2.

101. The complex of claim 74, wherein R and R' are taken together with the intervening atoms to form a 3- to 8-membered heterocyclyl.

102. The complex of claim 101, wherein R and R' are taken together with the intervening atoms to form a pyrrolidinyl.

103. The complex of claim 74, wherein R is H.

104. The complex of claim 1, wherein L is H.

105. The complex of claim 1, wherein the metal is zinc (Zn), iron (Fe), silver (Ag), cobalt (Co), copper (Cu), nickel (Ni), manganese (Mn), gold (Au), palladium (Pd), scandium (Sc), molybdenum (Mo), tungsten (W), chromium (Cr), vanadium (V), titanium (Ti), gallium (Ga), germanium (Ge), arsenic (As), selenium (Se), yttrium (Y), zirconium (Zr), niobium (Nb), technetium (Tc), ruthenium (Ru), rhodium (Rh), cadmium (Cd), indium (In), tin (Sn), antimony (Sb), hafnium (Hf), tantalum (Ta), rhenium (Re), osmium (Os), iridium (Ir), platinum (Pt), mercury (Hg), thallium (TI), lead (Pb), or bismuth (Bi).

106. The complex of claim 105, wherein the metal is Zn, Fe, Ag, Co, Cu, Ni, Mn, Au, Pd, Sc, Mo, W, Cr, orV.

107. The complex of claim 106, wherein the metal is Zn, Fe, Mn, Ni, Co, Cu, Sc, or Mo.

108. The complex of claim 106, wherein the metal is Zn(ll), Fe(ll), Fe(lll), Mn(ll), Mn(lll), Mn(IV), Mn(V), Mn(VI), Ni(ll), Ni(lll), Ag(l), Co(ll), Co(lll), Cu(l), Cu(ll), Au(l), Au(lll), Pd(ll), Sc(lll), Mo(ll), Mo(lll), Mo(IV), Mo(V), Mo(VI), W(ll), W(lll), W(IV), W(V), W(VI), Cr(ll), Cr(lll), Cr(IV), Cr(V), Cr(VI), V(ll), V(lll), V(IV), orV(V).

109. The complex of claim 108, wherein the metal is Zn(ll).

110. The complex of claim 108, wherein the metal is Fe(ll) or Fe(lll).

111. The complex of claim 108, wherein the metal is Mn(ll), Mn(lll), Mn(IV), Mn(V), or Mn(VI).

112. The complex of claim 108, wherein the metal is Ni(II) or Ni(III).

113. The complex of claim 108, wherein the metal is Ag (I).

114. The complex of claim 108, wherein the metal is Co(ll) or Co(lll).

115. The complex of claim 108, wherein the metal is Cu(l) or Cu(ll).

116. The complex of claim 108, wherein the metal is Au(l) or Au(lll).2025-12-15 117. The complex of claim 108, wherein the metal is Pd(ll).

118. The complex of claim 108, wherein the metal is Sc(lll).

119. The complex of claim 108, wherein the metal is Mo(ll), Mo(lll), Mo(IV), Mo(V), or Mo(VI) 120. The complex of claim 108, wherein the metal is W(ll), W(lll), W(IV), W(V), or W(VI).

121. The complex of claim 108, wherein the metal is Cr(ll), Cr(lll), Cr(IV), Cr(V), or Cr(VI).

122. The complex of claim 108, wherein the metal is V(ll), V(lll), V(IV), or V(V).

123. The complex of claim 108, wherein the metal is Zn(ll), Fe(ll), Fe(lll), Mn(ll), Mn(lll), Mn(IV), Ni(ll), Ni(lll), Co(ll), Cu(l), Cu(ll), Sc(lll), Mo(ll), Mo(lll), or Mo(IV).

124. The complex of claim 1, wherein the metal is a metal ion.

125. The complex of claim 1, wherein the complex is four-coordinate.

126. The complex of claim 125, having square planar geometry.

127. The complex of claim 125, having tetrahedral geometry.

128. The complex of claim 1, wherein the complex is five-coordinate.

129. The complex of claim 128, having square pyramidal or trigonal bipyramidal geometry.

130. The complex of claim 1, wherein the complex is six-coordinate.

131. The complex of claim 130, having octahedral geometry.

132. The complex of claim 1, further comprising one or more solvent molecules and / or coordinating anions coordinated to the metal.

133. The complex of claim 132, further comprising two or more solvent molecules and / or coordinating anions coordinated to the metal.

134. The complex of claim 1, in crystalline form.

135. The complex of claim 1, comprising no ionic interactions between the metal and the pharmacologically active agent.

136. A metal-drug coordination complex selected from Table 1, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, wherein M is Zn(ll), Fe(ll), Fe(lll), Mn(ll), Mn(lll), Mn(IV), Mn(V), Mn(VI), Ni(ll), Ni(lll), Ag(l), Co(ll), Co(lll), Cu(l), Cu(ll), Au(l), Au(lll), Pd(ll), Sc(lll), Mo(ll), Mo(lll), Mo(IV), Mo(V), Mo(VI), W(ll), W(lll), W(IV), W(V), W(VI), Cr(ll), Cr(lll), Cr(IV), Cr(V), Cr(VI), V(ll), V(lll), V(IV), orV(V).

137. The complex of claim 136, further comprising one or more solvent molecules and / or anions.

138. The complex of claim 137, further comprising two or more solvent molecules and / or anions.

139. A metal-drug coordination complex selected from Table 2, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

140. A metal-drug coordination complex selected from the group consisting of:2025-12-15or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

141. A pharmaceutical composition comprising the complex of any of claims 1 -140, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, and one or more pharmaceutically acceptable excipients.2025-12-15 142. The pharmaceutical composition of claim 141, formulated for oral, mucosal, rectal, transdermal, subcutaneous, intravenous, intramuscular, inhaled, or intranasal administration.

143. The pharmaceutical composition of claim 141, in unit dosage form.

144. The pharmaceutical composition of claim 143, comprising the complex in a total amount of between about 10 mg and about 300 mg.

145. The pharmaceutical composition of claim 141, further comprising one or more additional active compounds.

146. The pharmaceutical composition of claim 145, wherein the one or more additional active compounds are selected from the group consisting of amino acids, amino acid derivatives, amino acid analogs, amino acid mimetics, antioxidants, anti-inflammatory agents, neuroprotective agents, analgesic, antinociceptive, anti neuropathic agents, anxiolytic agents, antidepressant agents, anti-PTSD agents, empathogenic agents, psychedelic agents, dissociative agents, psychoplastogenic or plasticity-inducing agents, monoaminergic agents, serotonergic agents, monoamine oxidase inhibitors, nootropic and pro-cognitive agents, sedative or caiming agents, stimulant or wake-promoting agents, cannabinoids, terpenes, and vitamins.

147. The pharmaceutical composition of claim 145, wherein the one or more additional active compounds are selected from the group consisting of alpha lipoic acid, acetyl-L-carnitine, N-acetylcysteine, magnesium, zinc, vitamin C, vitamin E, nicotinamide, melatonin, omega-3-fatty acids, Co-Q10, 5-hydroxytryptophan, epigallocatechin gallate, and electrolytes.

148. A method of treating a medical condition in a subject, comprising administering to the subject the complex of any of claims 1-140, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof.

149. The method of claim 148, wherein the medical condition is a disease or disorder linked to dysregulation or inadequate functioning of serotonergic neurotransmission, dopaminergic neurotransmission, or noradrenergic neurotransmission.

150. The method of claim 148, wherein the medical condition is a mental, behavioral, or neurodevelopmental disorder.

151. The method of claim 150, wherein the medical condition is a neurodevelopmental disorder, schizophrenia or another primary psychotic disorder, catatonia, a mood disorder, an anxiety or fear-related disorders, an obsessive-compulsive or related disorder, a disorder specifically associated with stress, a dissociative disorder, a feeding or eating disorder, an elimination disorder, a disorder of bodily distress or bodily experience, a disorder due to substance use or addictive behavior, an impulse control disorder, a disruptive behavior or dissocial disorder, a personality disorder, a paraphilic disorder, a factitious disorder, a neurocognitive disorder, a mental or2025-12-15 behavioral disorder associated with pregnancy, childbirth or the puerperium, a sleep-wake disorder, or a sexual dysfunction.

152. The method of claim 148, wherein the complex is administered together with one or more sessions of psychotherapy.

153. The method of claim 148, wherein administration of the complex results in reduced adverse effect incidence or severity, as compared to administration of a comparator.

154. The method of claim 153, wherein the reduction in adverse effect incidence or severity comprises a reduction in the incidence or severity of any of inflammation, immunosuppression, oxidative stress, mitochondrial dysfunction, overall toxicity, neurotoxicity, cardiotoxicity, and renal toxicity.

155. The method of claim 154, wherein the reduction in adverse effect incidence or severity comprises a reduction in the incidence or severity of oxidative stress.

156. The method of claim 153, wherein the comparator is 3,4-methylenedioxymethamphetamine (MDMA).

157. A method of manufacturing the complex of any of claims 1 -140, comprising contacting a metal-containing precursor with the one or more pharmacologically active agents under reaction conditions suitable to form one or more coordinating interactions between the metal and the one or more pharmacologically active agents.

158. The method of claim 157, wherein the reaction conditions comprise solution-phase complexation conditions, hydrothermal conditions, solvothermal conditions, or mechanochemical conditions.

159. A complex of any of claims 1-140, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for use in treating a medical condition in a subject.

160. A pharmaceutical composition of any of claims 141-147 for use in treating a medical condition in a subject.

161. Use of the complex of any of claims 1 -140, or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof, for the manufacture of a medicament for treating a medical condition in a subject.

162. Use of the pharmaceutical composition of any of claims 141-147 for the manufacture of a medicament for treating a medical condition in a subject.

163. A crystalline polymorph of the complex of any of claims 1-141.

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