WO2025038666A2

WO2025038666A2 - Compounds and methods for treating addiction

Info

Publication number: WO2025038666A2
Application number: PCT/US2024/042162
Authority: WO
Inventors: Ian Jenkins; Robert TINDER; Vaishnavi Narayan
Original assignee: Gatc Health Corp
Current assignee: Gatc Health Corp
Priority date: 2023-08-13
Filing date: 2024-08-13
Publication date: 2025-02-20
Anticipated expiration: 2026-02-13
Also published as: WO2025038666A3

Abstract

Embodiments include therapeutic small molecules for use in treating addiction and neurological disorders. The therapeutic small molecules can act as 5-HT_2A receptor agonists and/or 5-HT₆ receptor agonists. Unlike conventional agonists, the compounds disclosed herein do not cause psychedelic side-effects. In aspects, the compounds are used to treat an ailment or addiction. In aspects, the compounds promote neuroplasticity.

Description

COMPOUNDS AND METHODS FOR TREATING ADDICTION

FIELD OF THE INVENTION

[0001] The invention relates generally to small molecule therapeutics, more particularly, to compounds and methods of treating addiction.

BACKGROUND

[0002] The term “opioid” refers to a substance that acts on opioid receptors to produce morphine-like effects. Opioids include the illegal drug heroin, synthetic opioids such as fentanyl, and pain relievers available legally by prescription, such as oxycodone (OxyContin®), hydrocodone (Vicodin®), codeine, morphine and others. Thiamine

[0003] Opioids can be classified according to their effect on opioid receptors. In this manner opioids can be considered as agonists, partial agonists and antagonists. In addition, opioids can be classified according to the type of opioid receptor at which they produce their effects. Classically, there are considered to be three opioid receptors. These receptors are all G-protein-coupled receptors, and were originally named mu (after morphine), delta (after vas deferens, the tissue within which it was first isolated) and kappa (after the first ligand to act at this receptor, ketocyclazocine). In 1996 the International Union of Pharmacology (IUPHAR) renamed the receptors OP1 (the delta receptor), OP2 (the kappa receptor) and OP3 (the mu receptor). In 2000, this nomenclature was again changed to DOP, KOP and MOP. Now, however, owing to the extensive literature previously using the Greek nomenclature for opioid receptors (5, K and p) IUPHAR recommends using this classification and the DOP, KOP and MOP classification of 2000. In 1994, a fourth G-protein-coupled endogenous opioid like receptor was found, and was subsequently named the nociceptin (NOP) receptor.

[0004] The classical opioid receptors are distributed widely within the central nervous system and, to a lesser extent, throughout the periphery, occupying sites within the vas deferens, knee joint, gastrointestinal tract, heart and immune system, amongst others. In clinical practice the stimulation of the differing opioid receptors produces a range of effects, which are often dependent upon the location of the receptor, along with analgesia. Agonists binding to MOP receptors may cause analgesia, but also sedation, respiratory depression, bradycardia, nausea and vomiting and a reduction in gastric motility. Activation of DOP receptors can cause spinal and supraspinal analgesia and reduce gastric motility, while KOP receptor stimulation may produce spinal analgesia, diuresis and dysphoria.

[0005] Opioid agonist analgesics are used to treat moderate to severe, chronic cancer pain, often in combination with nonsteroidal anti-inflammatory drugs (NSAIDs), as well as acute pain (e.g. , during recovery from surgery and breakthrough pain). Further, their use is increasing in the management of chronic, non-malignant pain.

[0006] A perennial problem with potent opioid agonists however is one of abuse by drug addicts. Drug addiction is a worldwide problem of which opioid dependence, notably of heroin, is a major component. The World Health Organization (WHO) estimates that there are approximately 4.3 million opioid addicts globally, with approximately 0.7 million in Europe and 0.3 million in the US and Canada.

[0007] Opioid dependence is a major health problem and long-term heroin use is connected to a substantially increased risk of premature death from drug overdoses, violence and suicide. Well-known complications of opioids include the phenomenon of both physical and psychological dependence and addiction, which can in turn lead to opioid misuse, abuse and diversion. More than 70% of the illegal users obtain opioids by stealing them during pharmacy robberies, purchasing them illegally on the black market, or receiving them from family or friends. These individuals seek to achieve a “high” from prescription medications by taking an excess number of pills orally or by crushing the pills, followed by snorting, smoking, or injecting the new altered formulation. The misuse or abuse of prescription opioid medications is a growing problem, with abuse rates having quadrupled in the decade from 1990 to 2000. The deaths associated with abuse and misuse of prescription pain drugs have also quadrupled between 1999 and 2011. Frequently death associated with the overdose of opioids occurs within an hour of the administration of the opioid due to respiratory suppression. [0008] Because the availability of opioids has increased, there are now more deaths and overdoses from prescription opioids than deaths from heroin overdoses. The increased availability of opioids was partially brought about by The Joint Commission on Accreditation of Healthcare Organizations (JCAHO) standards from 2000 that demands pain be addressed by healthcare providers as the fifth vital sign. The evaluation of pain was thus made equivalent to the evaluation of a patient's vital signs including the heartbeat, blood pressure, respiratory rate, and temperature. A 2012 study showed that physicians played an important role in prescription drug overdoses as they attempted to comply with Federal mandates, avoid malpractice claims, avoid decreased patient satisfaction scores (as patients began demanding more prescriptions for opioid pain medications), and avoid decreased reimbursement. The same study found that of 3,733 fatalities associated with prescription opioid drugs, the drugs that caused or contributed to nearly half of the deaths were prescribed to patients by physicians. This public health issue confounds the clinical utility of opioids. The extent of their efficacy in the treatment of pain when utilized on a chronic basis has not been definitively proven and has made long-term treatment of non-cancer pain with opioids controversial. Coupled with the abuse and addiction potential, clinical safety concerns and side effect profile, proper physician prescribing of opioids may be prevented, and result in inadequate pain management.

[0009] Though the bulk of the current research is focused on abuse deterrence, addiction avoidance and patient safety, prescription drug are still abused, overdoses occur and death rates continue to rise. It is apparent that conventional approaches are not successful in preventing addiction or deaths. The abuse deterrent developments have either been too difficult to manufacture or fail in clinical use. The CDC determined that abuse of prescription opioid drugs is an epidemic because it has led to a quadrupling of death rates in recent years.

[0010] T reatments for addiction vary but include efforts to deter psychological and/or physiological dependencies. The symptoms of withdrawal are a major reason for relapse and further prescription drug abuse. There are three available medications to treat opioid addiction: methadone, buprenorphine and naltrexone. These medications are generally more effecting when combined with counseling and other support. Successful, lifelong therapy to stay opioid-free usually involves longterm medication as well as counseling or talk therapy programs. Despite these medications, rates of relapse remain astonishingly high.

[0011] Opioid abuse continues to grow which contributes untold emotional, social and economic damage. Yet opioids remain the standard of care for surgical and chronic pain relief. Improved medications and methods are needed to treat addiction. Aspects of the present invention fulfill this need and provide further related advantages as described in the following summary.

SUMMARY OF THE INVENTION

[0012] The present disclosure solves the problems described above by providing compounds and methods for treating addiction. In aspects, the addictive substance is an opioid (e.g., fentanyl). In aspects, the compounds and methods reduce one or more of (a) the craving of an addictive substance, (b) the level of physical dependence of an addictive substance, (c) the tolerance of an addictive substance and/or (d) the rate of relapse.

[0013] Embodiments include a compound of Formula I:

R¹ is OH, OCH3 or OH linked to a C1 -C10 straight or branched alkyl,

R² is a halogen,

R³ is NH, NCH3 or N linked to a C1-C10 straight or branched alkyl,

[0014] Embodiments include a compound of Formula II:

R¹ is OH, OCH3 or OH linked to a C1 -C10 straight or branched alkyl, R² is a halogen,

R³ is NH, NCH3 or N linked to a C1-C10 straight or branched alkyl, n is 0, 1 , 2, 3 or 4.

[0015] Embodiments include a compound of D3 (GATC-1021), a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

Formula D3.

[0016] Embodiments include a compound identified herein, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

[0017] Embodiments also include methods of treating an ailment by administering a therapeutic amount of a compound of Formula I, Formula II or Formula D3. The ailment can be, for example, anxiety, inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, depression, Parkinson's disease, stroke, headaches, encephalitis, myasthenia gravis, depression, headaches (e.g., migraines), glaucoma, insomnia, fibromyalgia, a mood disorder (e.g., bipolar), epilepsy, anxiety and/or obsessive-compulsive disorder (OCD).

[0018] In embodiments, the compounds described herein are selective HT2A and HTe agonists. In aspects, the compounds do not have side effects of conventional agonists (e.g., psychedelic effects).

[0019] In embodiments, the compounds described herein can cross the blood brain barrier.

[0020] Embodiments include 5-HT2A receptor agonists that do not cause psychedelic side-effects. In aspects, the compounds are used to treat an ailment or addiction. In aspects, the compounds promote neuroplasticity.

[0021] In embodiments, the compounds described herein are useful in improving neuroplasticity. Another embodiment is a method of stimulating neuroplasticity in a subject wherein improving neuroplasticity prevents and/or treats an ailment such as a neurological disorder or addiction.

[0022] Embodiments include 5-HTe receptor agonists that do not cause psychedelic side-effects. In aspects, the compounds are used to treat an ailment or addiction. In aspects, the compounds promote neuroplasticity.

[0023] Embodiments include compounds that act as both 5-HT2A receptor agonists and 5-HTe receptor agonists.

[0024] Embodiments also include methods of modulating a G protein-coupled receptor (e.g., 5-HT2A and/or 5-HTe) to treat an ailment and/or an addiction.

[0025] In embodiments, the compounds described herein are provided as pro-drugs to improve absorption across the blood brain barrier. Accordingly, aspects include small molecule therapeutics that include an active agent and a pro-drug component. A therapeutic amount of the composition can be administered to treat an ailment or an addiction.

[0026] In aspects, the compounds described herein are administered with thiamine. In aspects, thiamine improves the safety profile of the compound (e.g., by allowing less compound to be administered without decreasing efficacy).

[0027] In aspects, the methods described herein include use of a therapeutic amount of thiamine and/or sulbutiamine. In aspects, this can increase the effectiveness and/or efficacy of the therapeutic.

[0028] In embodiments, the compounds and methods described herein are used to treat addiction. In aspects, the addiction is to an opioid (e.g., fentanyl, oxycontin, etc.), nicotine, cocaine, an opioid agonist or dependency on stimulants, nicotine, morphine, heroin, other opiates, amphetamines, cocaine, and/or alcohol.

[0029] In embodiments, the compounds and methods described herein are used to prevent or reduce the occurrence of an undesired behavior (e.g., tics).

[0030] In embodiments, the compounds and methods described herein are used to treat an ailment. The ailment can be, for example, anxiety, inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, depression, Parkinson's disease, stroke, headaches, encephalitis, myasthenia gravis, depression, headaches (e.g., migraines), glaucoma, insomnia, fibromyalgia, a mood disorder (e.g., bipolar), epilepsy, anxiety and/or obsessive-compulsive disorder (OCD). In aspects, the ailment is associated with 5-HT2A receptor activity and/or include 5-HTe receptor activity. [0031] Another embodiment is a method of improving neural function by administering a therapeutically effective amount of a compound as described herein.

[0032] In still another aspect, the present specification provides a use of the therapeutic small molecule or the pharmaceutical composition including the same in the preparation of drugs for the prevention or treatment of a neurological disorder or addiction.

[0033] In aspects, the therapeutic is administered to a patient as an inhalant. In aspects the inhalant is administered via nasal delivery.

[0034] In embodiments, the compounds described herein can stimulate limbic remodeling and/or neurite outgrowth.

[0035] Embodiments include methods of treating ailments (e.g., a neurological or brain disorder) by administering a compound described herein (e.g., GATC 1021). In aspects, the compound is administered with thiamine or pharmacological equivalent drug, or prodrug (e.g., sulbutiamine and benfotiamine).

[0036] In embodiments, treatment with sulbutiamine leads to lower absorption of the compounds described herein into the brain. As a result, co-administration of the drug with thiamine (or thiamine derivative) can produce an improved safety profile. Accordingly, embodiments include methods of improving the bioavailability and/or safety profile of a therapeutic by co-administration with thiamine or a thiamine derivative.

[0037] Embodiments include methods of treating ailments (e.g., a neurological or brain disorder) by administering a HT2A/HT6 agonist described herein. In aspects, the compound is administered with thiamine, or pharmacologically equivalent drug or prodrug.

[0038] In aspects, the methods described herein lead to a reduction in off target toxicity in HERG or A2A. [0039] In aspects, the methods described herein lead to HT2A/HT6 agonist levels in the brain that are attenuated from agonist administration alone.

[0040] In aspects, the methods described herein lead to restoration of the rate of gap junction degradation to homeostatic levels.

[0041] In aspects, GATC 1021 (and other compounds) bind to and act as antagonists on the M1 muscarinic receptor. This can result in altered clipping behavior and neurite remodeling leading to limbic remodeling in the brain. The mechanisms indicate that the M1 receptor is involved in addiction.

[0042] Other features and advantages of aspects of the present invention will become apparent from the following more detailed description, taken in conjunction with the accompanying drawings, which illustrate, by way of example, the principles of aspects of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

[0043] The accompanying drawings illustrate aspects of the present invention. In such drawings:

[0044] FIG. 1 depicts molecular signaling pathways regulated by the 5-HT2A receptor.

[0045] FIG. 2 depicts molecular signaling pathways regulated by the 5-HTe receptor.

[0046] FIG. 3 is a table of 5-HT2A/5-HT6 receptor agonists according to embodiments.

Definitions

[0047] Reference in this specification to "one embodiment/aspect" or "an embodiment/aspect" means that a particular feature, structure, or characteristic described in connection with the embodiment/aspect is included in at least one embodiment/aspect of the disclosure. The use of the phrase "in one embodiment/aspect" or "in another embodiment/aspect" in various places in the specification are not necessarily all referring to the same embodiment/aspect, nor are separate or alternative embodiments/aspects mutually exclusive of other embodiments/aspects. Moreover, various features are described which may be exhibited by some embodiments/aspects and not by others. Similarly, various requirements are described which may be requirements for some embodiments/aspects but not other embodiments/aspects. Embodiment and aspect can in certain instances be used interchangeably.

[0048] The terms used in this specification generally have their ordinary meanings in the art, within the context of the disclosure, and in the specific context where each term is used. Certain terms that are used to describe the disclosure are discussed below, or elsewhere in the specification, to provide additional guidance to the practitioner regarding the description of the disclosure. It will be appreciated that the same thing can be said in more than one way.

[0049] Consequently, alternative language and synonyms may be used for any one or more of the terms discussed herein. Nor is any special significance to be placed upon whether or not a term is elaborated or discussed herein. Synonyms for certain terms are provided. A recital of one or more synonyms does not exclude the use of other synonyms. The use of examples anywhere in this specification including examples of any terms discussed herein is illustrative only, and is not intended to further limit the scope and meaning of the disclosure or of any exemplified term. Likewise, the disclosure is not limited to various embodiments given in this specification.

[0050] Without intent to further limit the scope of the disclosure, examples of instruments, apparatus, methods and their related results according to the embodiments of the present disclosure are given below. Note that titles or subtitles may be used in the examples for convenience of a reader, which in no way should limit the scope of the disclosure. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In the case of conflict, the present document, including definitions, will control. [0051] The term “neurological disorder” broadly refers to a disorder of the nervous system. Neurological disorders can affect the brain as well as the nerves found throughout the human body and the spinal cord. Structural, biochemical or electrical abnormalities in the brain, spinal cord or other nerves can result in a range of symptoms. Neurological disorders include, for example, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, Parkinson's disease, stroke, headaches, encephalitis and myasthenia gravis.

[0052] The term “neurodegenerative disease” refers to a disease caused by the progressive loss of structure or function of neurons, in the process known as neurodegeneration. Such neuronal damage may ultimately involve cell death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. They encompass a wide range of conditions that result from progressive damage to cells and nervous system connections that are essential for mobility, coordination, strength, sensation, and cognition. Examples include: Alzheimer's disease and other memory disorders, ataxia, Huntington's disease, Parkinson's disease, motor neuron disease, multiple system atrophy, progressive supranuclear palsy, frontotemporal lobar degeneration, frontotemporal dementia; primary progressive aphasia; PNFA: progressive nonfluent aphasia; FTLD-U frontotemporal lobar degeneration with ubiquitin positive inclusions; AD: Alzheimer's Disease; MCI: mild cognitive impairment PD: Parkinson's Disease; DLB: dementia with Lewy bodies and lewy body disease.

[0053] The term “brain disorder” refers to a neurological disorder which affects the brain’s structure and function. Brain disorders can include, for example, Alzheimer’s, Parkinson’s disease, psychological disorder, depression, treatment resistant depression, addiction, anxiety, post-traumatic stress disorder (PTSD), suicidal ideation, major depressive disorder, bipolar disorder, schizophrenia, stroke, traumatic brain injury and substance use disorder. [0054] The term “addiction” can be defined as a biopsychosocial disorder characterized by compulsive engagement in rewarding stimuli despite adverse consequences. Addiction affects over 19.7 million people in the United States and presents a high financial and human toll. The total economic cost is greater than that of all types of diabetes and all cancers combined. These costs arise from, for example, the direct adverse effects of drugs and related healthcare costs, long-term complications, the loss of productivity and associated welfare costs, accidents, suicides, homicides and incarceration. To date there have been few effective pharmacological interventions and none that completely resolve the damage to the addicted brain.

[0055] The term “substance use disorder” or “SUD” can be defined as the persistent use of drugs despite substantial harm and adverse consequences. As an individual becomes increasingly dependent on a drug, discontinued use leads to withdrawal symptoms such as dysphoria. Substance use disorders are characterized by various mental/emotional, physical, and behavioral problems such as chronic guilt, an inability to reduce or stop consuming the substances despite repeated attempts, driving while intoxicated and physiological withdrawal symptoms. The development of dependence has been conceptualized as a neurobehavioral disorder that advances from impulsive drug use to compulsive drug abuse.

[0056] The term "behavioral addiction" can be defined as a compulsion to engage in a natural reward - which is a behavior that is inherently rewarding (i.e., desirable or appealing) - despite adverse consequences. Precl inical evidence has demonstrated that marked increases in the expression of AFosB through repetitive and excessive exposure to a natural reward induces the same behavioral effects and neuroplasticity as occurs in a drug addiction.

[0057] The brain disease model of addiction (BDMA) identifies addiction as a chronic relapsing brain disease suggesting that effective treatments to addiction include pharmaceutical and other medical interventions. BDMA holds that SUDs are chronic, relapsing brain diseases and that relapses are symptoms, and part of the expected course, of the disease. As with other diseases, SUDs can have multiple causes, including behavioral, environmental, and biological influences.

[0058] The term “neuroplasticity,” also known as neural plasticity, or brain plasticity, refers to the ability of neural networks in the brain to change through growth and reorganization. These changes range from individual neuron pathways making new connections, to systematic adjustments like cortical remapping. Examples of neuroplasticity include circuit and network changes that result from learning a new ability, environmental influences, practice and psychological stress. Neuroplasticity was once thought to manifest only during childhood, but recent research has demonstrated that many aspects of the brain can be altered (i.e., are "plastic") even through adulthood. However, the developing brain exhibits a higher degree of plasticity than the adult brain. Activity-dependent plasticity can have significant implications for healthy development, learning, memory and recovery from brain damage.

[0059] The term “prevent” and similar word such as “prevention,” “preventing” etc., refers to an approach for preventing the onset or recurrence of a disease or condition, (e.g., addiction, or relapse use or behavior) or preventing the occurrence or recurrence of the symptoms of a disease or condition, or optionally an approach for delaying the onset or recurrence of a disease or condition or delaying the occurrence or recurrence of the symptoms of a disease or condition.

[0060] The term “omics” refers to utilizing multiple molecular disciplines that involve the characterization of global sets of biological molecules such as DNAs, RNAs, proteins, and metabolites. For example, genomics investigates thousands of DNA sequences, transcriptomics investigates all or many gene transcripts, proteomics investigates large numbers of proteins, and metabolomics investigates large sets of metabolites. Omic data can include genomic data, transcriptomics, proteomics, epigenomics and metabolomics.

[0061] The term “historical data” refers to data (e.g. physiological measurements and actions of individuals) recorded and/or stored in a database that can be accessed for analysis and/or comparison. The data can be raw (e.g. sensor data) or processed (e.g. fused data). Historical data can include (a) data compiled from groups/populations of individuals and (b) data compiled from an individual person. For example, data can be recorded from healthy people and people with known ailments. An analysis of the data can indicate variations in physiological measurements that can be correlated with ailments. Likewise, data from an individual person can be recorded and stored. This can allow the system to identify patterns, variations and/or aberrations in activity for that particular person.

[0062] As used herein, "additional biomedical information" refers to one or more evaluations of an individual, other than using any of the biomarkers described herein, that are associated with health and/or susceptibility to diabetes. Accordingly, "additional biomedical information" includes any of the following: physical descriptors of an individual, the height, weight and/or BMI of an individual, the gender of an individual, the ethnicity of an individual, family history, smoking history, occupational history, etc. Additional biomedical information can be obtained from an individual using routine techniques known in the art, such as from the individual themselves by use of a routine patient questionnaire or health history questionnaire, etc., or from a medical practitioner, etc.

[0063] The term “formulation’’ as used herein refers to the antibodies disclosed herein and excipients combined together which can be administered and has the ability to bind to the corresponding receptors and initiate a signal transduction pathway resulting in the desired activity. The formulation can optionally comprise other agents.

[0064] The term "administration" refers to the introduction of an amount of a predetermined substance into a patient by a certain suitable method. The composition disclosed herein may be administered via any of the common routes, as long as it is able to reach a desired tissue, for example, but is not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, topical, intranasal, intrapulmonary, or intrarectal administration. However, since peptides are digested upon oral administration, active ingredients of a composition for oral administration should be coated or formulated for protection against degradation in the stomach.

[0065] The term “medicament,” “active agent” or “active ingredient” refers to a substance, compound, or molecule, which is biologically active or otherwise, induces a biological or physiological effect on a subject to which it is administered to. In other words, “active agent” or “active ingredient” refers to a component or components of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a primary active agent, or in other words, the component(s) of a composition to which the whole or part of the effect of the composition is attributed. An active agent can be a secondary agent, or in other words, the component(s) of a composition to which an additional part and/or other effect of the composition is attributed.

[0066] The term “pro-drug” refers a compound that includes chemical groups which, in vivo, can be converted and/or can be split off from the remainder of the molecule to provide for the active drug, a pharmaceutically acceptable salt thereof, or a biologically active metabolite thereof. Rather than administering a drug directly, a corresponding prodrug can be used to improve how the drug is absorbed, distributed, metabolized, and excreted. Pro-drugs are often designed to improve bioavailability when a drug itself is poorly absorbed from the gastrointestinal tract. A pro-drug may be used to improve how selectively the drug interacts with cells or processes that are not its intended target. This can reduce adverse or unintended effects of a drug.

[0067] The term “bioavailability” refers to the fraction of an administered dose of unchanged drug that reaches the systemic circulation. For example, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases due to incomplete absorption and first-pass metabolism. Bioavailability is one of the essential tools in pharmacokinetics, as bioavailability must be considered when calculating dosages for non-intravenous routes of administration. In an embodiment, the bioavailability of an agent is increased by converting it to a prodrug.

[0068] The term “half maximal effective concentration” or “ECso” refers to a measure of the concentration of a drug, antibody or toxicant which induces a biological response halfway between the baseline and maximum after a specified exposure time. More simply, ECso can be defined as the concentration required to obtain a 50% [...] effect and may be also written as [A]so. It is commonly used as a measure of a drug's potency and is expressed in molar units (M).

[0069] In an embodiment, a “subject” of diagnosis or treatment is, without limitation, a prokaryotic or a eukaryotic cell, a tissue culture, a tissue or an animal, e.g. a mammal, including a human. Non-human animals subject to diagnosis or treatment include, for example, without limitation, a simian, a murine, a canine, a leporid, such as a rabbit, livestock, sport animals, and pets.

[0070] The terms “treating,” “treatment” and the like are used herein, without limitation, to mean obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing a disorder or sign or symptom thereof, and/or may be therapeutic in terms of amelioration of the symptoms of the disease or infection, or a partial or complete cure for a disorder and/or adverse effect attributable to the disorder.

[0071] The term “prognosis” refers to the likely outcome or course of a disease and/or the chance of recovery or recurrence. This is in contrast to a “diagnosis” which refers to identifying an ailment or disease, usually from examining a subject. For example, addiction prognosis refers to whether the addiction will respond to treatment or mitigation efforts and/or the likelihood that it will progress.

[0072] The term “health evaluation” or “health assessment” refers to a plan of care that identifies the specific needs of a person and how those needs will be addressed by the healthcare system or healthcare provider. Conventionally, a health assessment follows an evaluation of a subject’s health status by performing a physical exam after taking a health history.

[0073] The term "biomarker" refers generally to a DNA, RNA, protein, carbohydrate, or glycolipid-based molecular marker, the expression or presence of which in a sample can be detected by standard methods (or methods disclosed herein) and is predictive or prognostic of the effective responsiveness or sensitivity of a mammalians subject with an ailment. Biomarkers may be present in a test sample but absent in a control sample, absent in a test sample but present in a control sample, or the amount or of biomarker can differ between a test sample and a control sample. For example, protein biomarkers can be present in such a sample, but not in a control sample, or certain biomarkers are seropositive in the sample, but seronegative in a control sample. Also, expression of such a biomarker may be determined to be higher than that observed from a control sample. The terms "marker" and "biomarker" are used herein interchangeably.

[0074] The term “physiological event” refers to a response or reaction of the body to a stimulus. Most are automatic/instinctive physiological responses. The healthy state of the body depends upon the integrity of various organ systems. The organ systems in the body function in a particular manner constantly. The mechanisms, by which the organ systems of the body function, can be referred to as “physiological mechanisms.” Physiological mechanisms explain any health-related events or outcomes. Physiological mechanisms can be altered voluntarily. For example, exercise causes alteration in the cardiac physiology of resting state.

[0075] The term “stimulant” refers to a substance that increases activity of the central nervous system and/or the body. Stimulants are widely used as prescription medicines as well as without a prescription (either legally or illicitly) as performanceenhancing or recreational drugs. Most stimulants exert their activating effects by enhancing catecholamine neurotransmission. Common stimulants include, amphetamine, caffeine, ephedrine, MDMA, MDPV, mephedrone, methamphetamine, methylphenidate, cocaine, phenylpropanolamine, propylhexedrine, pseudoephedrine, Catha edulis (Khat) and modafinil. [0076] The term “5-HT2A receptor” refers to a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor (GPCR). The 5-HT2A receptor is a cell surface receptor but has several intracellular locations. 5-HT is short for 5-hydroxy-tryptamine or serotonin. This is the main excitatory receptor subtype among the GPCRs for serotonin, although 5-HT2A may also have an inhibitory effect on certain areas such as the visual cortex and the orbitofrontal cortex.

[0077] The term “5-HT2A receptor agonist” refers to a substance that initiates a physiological response when combined with the 5-HT2A receptor. Activation of the 5- HT2A receptor is necessary for the effects of the "classic" psychedelics like LSD, psilocin and mescaline, which act as full or partial agonists at this receptor, and represent the three main classes of 5-HT2A agonists, the ergolines, tryptamines and phenethylamines, respectively. A very large family of derivatives from these three classes has been developed, and their structure-activity relationships have been extensively researched. Agonists acting at 5-HT2A receptors located on the apical dendrites of pyramidal cells within regions of the prefrontal cortex are believed to mediate hallucinogenic activity.

[0078] The term “5HTe receptor” refers to a subtype of 5HT receptor that binds the endogenous neurotransmitter serotonin ("5-HT" = 5-hydroxytryptamine, also known as serotonin). It is a G protein-coupled receptor (GPCR) that is coupled to Gs and mediates excitatory neurotransmission. HTR6 denotes the human gene encoding for the receptor.

[0079] The term “5-HTe receptor agonist” refers to a substance that initiates a physiological response when combined with the 5-HTe receptor.

[0080] The term “sulbutiamine” refers to a synthetic derivative of thiamine (vitamin B1). It can be used to treat thiamine deficiency. Because thiamine deficiency causes problems with memory and other cognitive functions, thiamine and analogs like sulbutiamine have been studied in clinical trials for age-associated cognitive decline. Sulbutiamine has been explored in clinical trials as a potential treatment for chronic fatigue syndrome. It is sold commercially under the brand names Arcalion™ and Enerion™.

[0081] In aspects, thiamine is administered in a prodrug form. Recent efforts have focused on developing thiamine derivatives with better bioavailability. These efforts led to the discovery of allicin (diallyl thiosulfinate), sulbutiamine, fursultiamine (thiamine tetrahydrofurfuryl disulfide) and benfotiamine. These compounds are hydrophobic, easily pass from the intestines to the bloodstream, and are reduced to thiamine by cysteine or glutathione.

[0082] The term “tropomyosin receptor kinase B” or “TrkB” also known as tyrosine receptor kinase B, or BDNF/NT-3 growth factors receptor or neurotrophic tyrosine kinase, receptor, type 2 is a protein that in humans is encoded by the NTRK2 gene. TrkB is a receptor for brain-derived neurotrophic factor (BDNF). The TrkB receptor is part of the large family of receptor tyrosine kinases.

[0083] The term “blood-brain barrier” or “BBB” refers to a highly selective semipermeable border of endothelial cells that prevents solutes in the circulating blood from non-selectively crossing into the extracellular fluid of the central nervous system where neurons reside. The blood-brain barrier is formed by endothelial cells of the capillary wall, astrocyte end-feet ensheathing the capillary, and pericytes embedded in the capillary basement membrane. This system allows the passage of some small molecules by passive diffusion, as well as the selective and active transport of various nutrients, ions, organic anions, and macromolecules such as glucose and amino acids that are crucial to neural function.

[0084] The term “omics” refers to comprehensive approaches for analysis of complete genetic or molecular profiles of humans and other organisms. Since the process of mapping and sequencing the human genome began, new technologies have made it possible to obtain a huge number of molecular measurements within a tissue or cell. These technologies can be applied to a biological system of interest to obtain a snapshot of the underlying biology at a resolution that has never before been possible. Broadly speaking, the scientific fields associated with measuring such biological molecules in a high-throughput way are called “omics.”

[0085] The term “combination therapy” refers to a method of treating a disease or disorder, wherein two or more different pharmaceutical agents are administered in overlapping regimens so that the subject is simultaneously exposed to both agents. For example, the compounds of the invention can be used in combination with other pharmaceutically active compounds. The compounds of the invention can be administered simultaneously (as a single preparation or separate preparation) or sequentially to the other drug therapy. In general, a combination therapy envisions administration of two or more drugs during a single cycle or course of therapy.

[0086] A compound of a given Formula (e.g. , the “compound of Formula D3”) is intended to encompass the compounds of the disclosure, and the pharmaceutically acceptable salts, pharmaceutically acceptable esters, hydrates, polymorphs, and prodrugs of such compounds. Additionally, the compounds of the disclosure may possess one or more asymmetric centers and can be produced as a racemic mixture or as individual enantiomers or diastereoisomers. The number of stereoisomers present in any given compound of a given Formula depends upon the number of asymmetric centers present (there are 2n stereoisomers possible where n is the number of asymmetric centers). The individual stereoisomers may be obtained by resolving a racemic or non-racemic mixture of an intermediate at some appropriate stage of the synthesis, or by resolution of the compound by conventional means.

The individual stereoisomers (including individual enantiomers and diastereoisomers) as well as racemic and non-racemic mixtures of stereoisomers are encompassed within the scope of the present invention, all of which are intended to be depicted by the structures of this specification unless otherwise specifically indicated.

[0087] The term “pharmaceutical composition” is intended to include the combination of an active agent (i.e., a prodrug therapeutic) with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. In one aspect, the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed. [0088] The term “isomer” refers to different compounds that have the same molecular formula. Isomers include stereoisomers, enantiomers, and diastereomers. Similarly, “stereoisomers” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non- superimposable mirror images of each other. A 1 :1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(+)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0089] The term “pharmaceutically acceptable salt” refers to an acid or base salt that is generally considered in the art to be suitable for use in contact with the tissues of human beings or animals without excessive toxicity, irritation, allergic response, or other problem or complication. Such salts include mineral and organic acid salts of basic residues such as amines, as well as alkali or organic salts of acidic residues such as carboxylic acids. Specific pharmaceutical salts include, but are not limited to, salts of acids such as hydrochloric, phosphoric, hydrobromic, malic, glycolic, fumaric, sulfuric, sulfamic, sulfanilic, formic, toluenesulfonic, methanesulfonic, benzene sulfonic, ethane disulfonic, 2-hydroxyethylsulfonic, nitric, benzoic, 2- acetoxybenzoic, citric, tartaric, lactic, stearic, salicylic, glutamic, ascorbic, pamoic, succinic, fumaric, maleic, propionic, hydroxymaleic, hydroiodic, phenylacetic, alkanoic such as acetic, HOOC— (CH2)n— COOH where n is 0-4, and the like. Similarly, pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium and ammonium. In general, a pharmaceutically acceptable acid or base salt can be synthesized from a parent compound that contains a basic or acidic moiety by any conventional chemical method. For example, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in an appropriate solvent.

[0090] The term “pharmaceutical composition” is intended to include the combination of an active agent with a carrier, inert or active, in a sterile composition suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo. In one aspect, the pharmaceutical composition is substantially free of endotoxins or is non-toxic to recipients at the dosage or concentration employed.

[0091] The term “neurite outgrowth” refers to a process in which developing neurons create new projections as they grow in response to guidance cues. It is a fundamental process in neuronal differentiation and is important in the study of normal development and regeneration. It is also used to study how neurite outgrowth is inhibited or stimulated in disorders such as Alzheimer's disease and Parkinson's disease.

[0092] As applicable, the terms "about" or "generally", as used herein in the specification and appended claims, and unless otherwise indicated, means a margin of +/- 20%. Also, as applicable, the term "substantially" as used herein in the specification and appended claims, unless otherwise indicated, means a margin of +/- 10%. It is to be appreciated that not all uses of the above terms are quantifiable such that the referenced ranges can be applied.

[0093] Many known and useful compounds and the like can be found in Remington’s Pharmaceutical Sciences (13^th Ed), Mack Publishing Company, Easton, PA— a standard reference for various types of administration. As used herein, the term “formulation(s)” means a combination of at least one active ingredient with one or more other ingredients, also commonly referred to as excipients, which may be independently active or inactive. The term “formulation” may or may not refer to a pharmaceutically acceptable composition for administration to humans or animals and may include compositions that are useful intermediates for storage or research purposes.

[0094] As the patients and subjects of the invention method are, in addition to humans, veterinary subjects, formulations suitable for these subjects are also appropriate. Such subjects include livestock and pets as well as sports animals such as horses, greyhounds, and the like.

DETAILED DESCRIPTION [0095] Embodiments of the invention relate to the fields of addiction and mental health. Particular embodiments include compounds and methods for treating mental health ailments and/or addictions. Specifically, aspects of the invention include novel compounds that are selective HT2A and HTe receptor agonists. The compounds were validated in silico and screened for targeting, ADME (i.e., absorption, distribution, metabolism and excretion) and toxicity.

[0096] The 5-HT2A receptor is a widely expressed Gq-coupled protein receptor (GCPR) that triggers a range of intracellular pathways. Central nervous system (CNS) expression of the 5-HT2A receptor is most extensive in the cortex, hippocampus, basal ganglia, and forebrain. Because these areas of the CNS are primarily involved with cognitive function and social interactions, 5-HT2A is implicated in the pathology of several cognitive and learning disorders including schizophrenia, obsessive-compulsive disorder (OCD) and depression. The highest density of 5- HT2A receptors is found in levels 1 , 4, and 5a of the cortex, with medial expression levels in the olfactory bulb, brainstem, and dorsal horn of the spinal cord. 5-HT2A is also expressed by a range of CNS cells, including pyramidal neurons and glia, and has several intracellular locations.

[0097] FIG. 1 depicts 5-HT2A receptor signaling pathways in mesangial kidney cells. The 5-HT2AR is coupled to PLC and PLD via Gaq protein and plays a role in the control of cell proliferation and fibrosis.

[0098] The 5-HTe receptor is a G-protein-linked receptor, and is expressed primarily in the striatum, olfactory tubercle, frontal and entorhinal cortex, nucleus accumbens, hippocampus and molecular layer of the cerebellum. Pharmacological blockade of 5-HTe receptor had been shown to produce promnesic or antiamnesic effects (or both) in a number of memory tasks, and emergent evidence indicates that its agonists also seem facilitate memory in diverse memory tasks; the reasons for apparent paradox of promnesic and/or anti amnesic effects of 5-HTe receptor agonists and antagonists are unclear. The development of potent and selective 5- HTe receptor antagonists has been crucial in the clarification of the role of 5-HTe receptor role on memory; in addition, the findings that 5-HTe receptor agonists can improve memory are providing new insights.

[0099] FIG. 2 depicts 5-HTe receptor signaling pathways. The 5-HTe receptor is positively coupled to AC/cAMP pathway via Gas protein. Its stimulation inhibits K+ channel (GIRK) conductance in neurons and activates kinases via a direct interaction of the receptor C-terminus with interacting proteins, which produces ERK phosphorylation or Jun translocation to the nucleus.

[00100] Applicants have discovered that agonists of 5-HT2A receptor and 5-HTe receptor can be used therapeutically to treat mental health ailments and addiction. Accordingly, embodiments include selective HT2A and HTe agonists that can be used therapeutically. In aspects, the compounds are capable of crossing the blood brain barrier to reach a target tissue.

[00101] Further validation of the compounds indicated the need for brain-available thiamine as a co-factor in fentanyl addiction treatment. Applicants evaluated target molecules for activity that would be selective HT2A and HTSA agonists along with coadministration of the pro-drug sulbutiamine (see below examples).

Therapeutic Compounds

[00102] Embodiments include a compound of Formula I:

R¹ is OH, OCH3 or OH linked to a C1 -C10 straight or branched alkyl,

R² is a halogen,

R³ is NH, NCH3 or N linked to a C1-C10 straight or branched alkyl,

[00103] Embodiments include a compound of Formula II:

R¹ is OH, OCHs or OH linked to a C1 -C10 straight or branched alkyl, R² is a halogen,

[00104] Embodiments include a compound of D3 (GATC-1021), a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

Formula D3

[00105] Embodiments include a compound of GATC-1002, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

GATC-1002

[00106] Embodiments include a compound of GATC-1005, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof. GATC-1005

[00107] Embodiments include a compound of GATC-1007, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

GATC-1007

[00108] Embodiments include a compound of GATC-1010, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

[00109] Embodiments include a compound of GATC-1011 , a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

[00110] Embodiments include a compound of GATC-1013, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

GATC-1013

[00111] Embodiments include a compound of GATC-1015, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

GATC-1015

[00112] Embodiments include a compound of GATC-1016, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof. GATC-1016

[00113] Embodiments include a compound of GATC-1020, a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

[00114] Embodiments include a compound of GATC-1021 , a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

[00115] The compounds may be provided and/or administered as a pharmaceutically acceptable salt, a solvate, a tautomer, an isomer or a deuterated analog thereof.

Methods of Treatment

[00116] Methods for treating, preventing or ameliorating a disease, disorder, a condition, an addiction or a symptom thereof or a condition related thereto are provided herein. Preferred, but non-limiting embodiments are directed to methods for treating, preventing, inhibiting or ameliorating a disease, disorder, a condition, an addiction or a symptom described below. [00117] Generally, a subject is provided with an effective amount of a compound as described herein (see FIG. 3). As used herein, an “effective amount” or a “therapeutically effective amount” of a substance is that amount sufficient to affect a desired biological or psychological effect, such as beneficial results, including clinical results. For example, in the context of treating addiction using the methods of the present invention, an effective amount of a compound D3 is that amount sufficient to cause the subject to reduce or discontinue use of an addictive agent (e.g., fentanyl). In the case of an addictive behavior, an effective amount of a compound of D3 is an amount sufficient to cause the subject to reduce or discontinue the addictive behavior.

[00118] To prepare pharmaceutical compositions described herein can be mixed with a pharmaceutical acceptable carrier, adjuvant and/or excipient, according to conventional pharmaceutical compounding techniques. Pharmaceutically acceptable carriers that can be used in the present compositions encompass any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, and emulsions, such as an oil/water or water/oil emulsion, and various types of wetting agents. The compositions can additionally contain solid pharmaceutical excipients such as starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, etc. Liquid and semisolid excipients can be, for example, glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols. The compositions also can include stabilizers and preservatives.

[00119] It is understood that the invention encompasses the use, where applicable, of stereoisomers, diastereomers and optical stereoisomers of the compounds of the invention, as well as mixtures thereof. Additionally, it is understood that stereoisomers, diastereomers, and optical stereoisomers of the compounds of the invention, and mixtures thereof, are within the scope of the invention. By way of non-limiting example, the mixture may be a racemate or the mixture may comprise unequal proportions of one particular stereoisomer over the other. Additionally, the compounds can be provided as a substantially pure stereoisomers, diastereomers and optical stereoisomers (such as epimers).

[00120] The compounds described herein can be asymmetric (e.g. , having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended to be included within the scope of the invention unless otherwise indicated. Compounds that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods of preparation of optically active forms from optically active starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds are also included within the scope of the invention and can be isolated as a mixture of isomers or as separated isomeric forms. Where a compound is capable of stereoisomerism, all such isomers are contemplated.

[00121] Compounds may also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Examples of prototropic tautomers include, but are not limited to, ketoneenol pairs, amide-imidic acid pairs, lactam-lactim pairs, amide-imidic acid pairs, enamine-imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system including, but not limited to, 1 H- and 3H-imidazole, 1 H-, 2H- and 4H-1 , 2 ,4-triazole, 1 H- and 2H-isoindole, and 1 H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[00122] Compounds also include hydrates and solvates, as well as anhydrous and non-solvated forms. Compounds can also include all isotopes of atoms occurring in the intermediates or final compounds. Isotopes include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium.

[00123] In some embodiments, the compounds, or salts thereof, are substantially isolated. Partial separation can include, for example, a composition enriched in the compound of the invention. Substantial separation can include compositions containing at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, or at least about 99% by weight of the compound of the invention, or salt thereof. Methods for isolating compounds and their salts are routine in the art.

[00124] One or more of the compounds described herein can be administered by any method known in the art, including, for example, intranasal, oral, transdermal, ocular, intraperitoneal, inhalation, intravenous, ICV, intracisternal injection or infusion, subcutaneous, implant, vaginal, sublingual, urethral (e.g., urethral suppository), subcutaneous, intramuscular, intravenous, rectal, sub-lingual, mucosal, ophthalmic, spinal, intrathecal, intra-articular, intra-arterial, sub-arachinoid, bronchial and lymphatic administration. A topical formulation can be in the form of gel, ointment, cream, aerosol, etc. An intranasal formulation can be delivered as a spray or in a drop. A prodrug formulation can be administered via a transdermal patch or iontophoresis. A formulation for inhalation can be delivered using a nebulizer or similar device. Compositions can also take the form of tablets, pills, capsules, semisolids, powders, sustained-release formulations, solutions, suspensions, elixirs, aerosols or any other appropriate compositions.

[00125] In another aspect, certain embodiments are directed to a sustained release drug delivery platform that releases a therapeutic compound or compounds disclosed and made as a formulation described herein over a period of, without limitation, about 3 days after administration, about 7 days after administration, about 10 days after administration, about 15 days after administration, about 20 days after administration, about 25 days after administration, about 30 days after administration, about 45 days after administration, about 60 days after administration, about 75 days after administration, or about 90 days after administration. In other aspects of this embodiment, a sustained release drug delivery platform releases a therapeutic compound or compounds disclosed herein with substantially first order release kinetics over a period of, without limitation, at least 3 days after administration, at least 7 days after administration, at least 10 days after administration, at least 15 days after administration, at least 20 days after administration, at least 25 days after administration, at least 30 days after administration, at least 45 days after administration, at least 60 days after administration, at least 75 days after administration, or at least 90 days after administration.

[00126] The therapeutic agents in the pharmaceutical compositions may be formulated in a "therapeutically effective amount" or a "prophylactically effective amount". A "therapeutically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the recombinant vector may vary depending on the condition to be treated, the severity and course of the condition, the mode of administration, whether the antibody or agent is administered for preventive or therapeutic purposes, the bioavailability of the particular agent(s), the ability of the agent to elicit a desired response in the individual, previous therapy, the age, weight and sex of the patient, the patient's clinical history and response to the antibody, the type of the agent used, discretion of the attending physician, etc. A therapeutically effective amount is also one in which any toxic or detrimental effects of the recombinant vector is outweighed by the therapeutically beneficial effects. A "prophylactically effective amount" refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result.

Administration

[00127] Wide variations in the necessary effective amount are to be expected in view of the differing efficiencies of the various routes of administration. For example, oral administration of a prodrug formulation disclosed herein generally would be expected to require higher dosage levels than administration by inhalation. Similarly, systemic administration of a prodrug formulation disclosed herein would be expected to require higher dosage levels than a local administration. Variations in these dosage levels can be adjusted using standard empirical routines of optimization, which are well-known to a person of ordinary skill in the art. The precise therapeutically effective dosage levels and patterns are preferably determined by the attending physician in consideration of the above-identified factors. One skilled in the art will recognize that the condition of the individual can be monitored throughout the course of therapy and that the effective amount of a therapeutic disclosed herein that is administered can be adjusted accordingly.

[00128] As a general proposition, a therapeutically effective amount or prophylactically effective amount of the agent will be administered in a range from about 1 ng/kg body weight/day to about 100 mg/kg body weight/day whether by one or more administrations. In a particular embodiment, each agent is administered in the range of from about 1 ng/kg body weight/day to about 10 mg/kg body weight/day, about 1 ng/kg body weight/day to about 1 mg/kg body weight/day, about 1 ng/kg body weight/day to about 100 g/kg body weight/day, about 1 ng/kg body weight/day to about 10 g/kg body weight/day, about 1 ng/kg body weight/day to about 1 g/kg body weight/day, about 1 ng/kg body weight/day to about 100 ng/kg body weight/day, about 1 ng/kg body weight/day to about 10 ng/kg body weight/day, about 10 ng/kg body weight/day to about 100 mg/kg body weight/day, about 10 ng/kg body weight/day to about 10 mg/kg body weight/day, about 10 ng/kg body weight/day to about 1 mg/kg body weight/day, about 10 ng/kg body weight/day to about 100 g/kg body weight/day, about 10 ng/kg body weight/day to about 10 mg/kg body weight/day, about 10 ng/kg body weight/day to about 1 mg/kg body weight/day, 10 ng/kg body weight/day to about 100 ng/kg body weight/day, about 100 ng/kg body weight/day to about 100 mg/kg body weight/day, about 100 ng/kg body weight/day to about 10 mg/kg body weight/day, about 100 ng/kg body weight/day to about 1 mg/kg body weight/day, about 100 ng/kg body weight/day to about 100 mg/kg body weight/day, about 100 ng/kg body weight/day to about 10 mg/kg body weight/day, about 100 ng/kg body weight/day to about 1 mg/kg body weight/day, about 1 mg/kg body weight/day to about 100 mg/kg body weight/day, about 1 mg/kg body weight/day to about 10 mg/kg body weight/day, about 1 mg/kg body weight/day to about 1 mg/kg body weight/day, about 1 mg /kg body weight/day to about 100 mg/kg body weight/day, about 1 mg /kg body weight/day to about 10 mg/kg body weight/day, about 10 mg/kg body weight/day to about 100 mg/kg body weight/day, about 10 mg/kg body weight/day to about 10 mg/kg body weight/day, about 10 mg/kg body weight/day to about 1 mg/kg body weight/day, about 10 mg/kg body weight/day to about 100 mg/kg body weight/day, about 100 mg/kg body weight/day to about 100 mg/kg body weight/day, about 100 mg/kg body weight/day to about 10 mg/kg body weight/day, about 100 mg/kg body weight/day to about 1 mg/kg body weight/day, about 1 mg/kg body weight/day to about 100 mg/kg body weight/day, about 1 mg/kg body weight/day to about 10 mg/kg body weight/day, about 10 mg/kg body weight/day to about 100 mg/kg body weight/day.

[00129] In other embodiments, each agent is administered in the range of about 10 ng to about 100 ng per individual administration, about 10 ng to about 1 g per individual administration, about 10 ng to about 10 g per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1 mg per individual administration, about 10 ng to about 10 mg per individual administration, about 10 ng to about 100 mg per individual administration, about 10 ng to about 1000 mg per individual administration, about 10 ng to about 10,000 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1 mg per individual administration, about 100 ng to about 10 mg per individual administration, about 100 ng to about 100 mg per individual administration, about 100 ng to about 1000 mg per injection, about 100 ng to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 5 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1000 mg per individual administration, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1 mg per individual administration, about 10 mg to about 50 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per individual administration, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1 mg per individual administration, about 100 mg to about 10 mg per individual administration, about 100 mg to about 500 mg per individual administration, about 100 mg to about 1000 mg per individual administration, about 100 mg to about 10,000 mg per individual administration, about 1 mg to about 10 mg per individual administration, about 1 mg to about 100 mg per individual administration, about 1 mg to about 1000 mg per individual administration, about 1 mg to about 10,000 mg per individual administration, about 10 mg to about 100 mg per individual administration, about 10 mg to about 1000 mg per individual administration, about 10 mg to about 10,000 mg per individual administration, about 100 mg to about 1000 mg per individual administration, about 100 mg to about 5,000 mg per individual administration and about 1000 mg to about 10,000 mg per individual administration. The agent may be administered daily, every 2, 3, 4, 5, 6 or 7 days, or every 1 , 2, 3 or 4 weeks.

[00130] In other embodiments, each agent is administered in the range of about 10 ng to about 100 ng per injection, about 10 ng to about 1 g per injection, about 10 ng to about 10 g per injection, about 10 ng to about 100 mg per injection, about 10 ng to about 1 mg per injection, about 10 ng to about 10 mg per injection, about 10 ng to about 100 mg per injection, about 10 ng to about 1000 mg per injection, about 10 ng to about 10,000 mg per injection, about 100 ng to about 1 mg per injection, about 100 ng to about 10 mg per injection, about 100 ng to about 100 mg per injection, about 100 ng to about 1 mg per injection, about 100 ng to about 10 mg per injection, about 100 ng to about 100 mg per injection, about 100 ng to about 1000 mg per injection, about 100 ng to about 10,000 mg per injection, about 1 mg to about 10 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 5 mg per injection, about 1 mg to about 10 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per injection, about 10 mg to about 100 mg per injection, about 10 mg to about 1 mg per injection, about 10 mg to about 50 mg per injection, about 10 mg to about 100 mg per injection, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per injection, about 100 mg to about 1 mg per injection, about 100 mg to about 10 mg per injection, about 100 mg to about 500 mg per injection, about 100 mg to about 1000 mg per injection, about 100 mg to about 10,000 mg per injection, about 1 mg to about 10 mg per injection, about 1 mg to about 100 mg per injection, about 1 mg to about 1000 mg per injection, about 1 mg to about 10,000 mg per injection, about 10 mg to about 100 mg per injection, about 10 mg to about 1000 mg per injection, about 10 mg to about 10,000 mg per injection, about 100 mg to about 1000 mg per injection, about 100 mg to about 5,000 mg per injection and about 1000 mg to about 10,000 mg per injection. The agent may be injected hourly, bi-hourly , tri-hourly , every 90 minutes, every two hours, every three hours, every four hours, twice daily, three times daily, four times daily, five times daily, six times daily, seven times daily, eight times daily, every 2, 3, 4, 5, 6 or 7 days, or every 1 , 2, 3 or 4 weeks.

[00131] In other particular embodiments, the amount of the agent may be administered at a dose of about 0.0006 mg/day, 0.001 mg/day, 0.003 mg/day, 0.006 mg/day, 0.01 mg/day, 0.03 mg/day, 0.06 mg/day, 0.1 mg/day, 0.3 mg/day, 0.6 mg/day, 1 mg/day, 3 mg/day, 6 mg/day, 10 mg/day, 30 mg/day, 60 mg/day, 100 mg/day, 300 mg/day, 600 mg/day, 1000 mg/day, 2000 mg/day, 5000 mg/day or 10,000 mg/day. As expected, the dosage will be dependent on the condition, size, age and condition of the patient.

[00132] In other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces the prevalence or likelihood of relapse by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces the prevalence or likelihood of relapse from, e.g., about 5% to about 100%, about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[00133] A pharmaceutical composition disclosed herein is in an amount sufficient to allow customary administration to an individual. In aspects of this embodiment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of a pharmaceutical composition. In other aspects of this embodiment, a pharmaceutical composition disclosed herein may be, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 ,000 mg, at least 1 , 100 mg, at least 1 ,200 mg, at least 1 ,300 mg, at least 1 ,400 mg, or at least 1 ,500 mg of a pharmaceutical composition. In yet other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1 ,000 mg, about 850 mg to about 1 ,200 mg, or about 1 ,000 mg to about 1 ,500 mg. In still other aspects of this embodiment, a pharmaceutical composition disclosed herein may be in the range of, e.g., about 10 mg to about 250 mg, about 10 mg to about 500 mg, about 10 mg to about 750 mg, about 10 mg to about 1 ,000 mg, about 10 mg to about 1 ,500 mg, about 50 mg to about 250 mg, about 50 mg to about 500 mg, about 50 mg to about 750 mg, about 50 mg to about 1 ,000 mg, about 50 mg to about 1 ,500 mg, about 100 mg to about 250 mg, about 100 mg to about 500 mg, about 100 mg to about 750 mg, about 100 mg to about 1 ,000 mg, about 100 mg to about 1 ,500 mg, about 200 mg to about 500 mg, about 200 mg to about 750 mg, about 200 mg to about 1 ,000 mg, about 200 mg to about 1 ,500 mg, about 5 mg to about 1 ,500 mg, about 5 mg to about 1 ,000 mg, or about 5 mg to about 250 mg. [00134] A pharmaceutical composition disclosed herein can also include an effective amount of thiamine and/or sulbutiamine. In aspects, a pharmaceutical composition disclosed herein can include, e.g., at least 5 mg, at least 10 mg, at least 15 mg, at least 20 mg, at least 25 mg, at least 30 mg, at least 35 mg, at least 40 mg, at least 45 mg, at least 50 mg, at least 55 mg, at least 60 mg, at least 65 mg, at least 70 mg, at least 75 mg, at least 80 mg, at least 85 mg, at least 90 mg, at least 95 mg, or at least 100 mg of thiamine and/or sulbutiamine in a pharmaceutical composition. In other aspects, a pharmaceutical composition disclosed herein can include, e.g., at least 5 mg, at least 10 mg, at least 20 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, at least 500 mg, at least 600 mg, at least 700 mg, at least 800 mg, at least 900 mg, at least 1 ,000 mg, at least 1 , 100 mg, at least 1 ,200 mg, at least 1 ,300 mg, at least 1 ,400 mg, or at least 1 ,500 mg of thiamine and/or sulbutiamine. In yet other aspects, a pharmaceutical composition disclosed herein can include thiamine and/or sulbutiamine in the range of, e.g., about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 150 mg, about 100 mg to about 250 mg, about 150 mg to about 350 mg, about 250 mg to about 500 mg, about 350 mg to about 600 mg, about 500 mg to about 750 mg, about 600 mg to about 900 mg, about 750 mg to about 1 ,000 mg, about 850 mg to about 1 ,200 mg, or about 1 ,000 mg to about 1 ,500 mg.

[00135] A pharmaceutical composition disclosed herein may comprise a solvent, emulsion or other diluent in an amount sufficient to dissolve a pharmaceutical composition disclosed herein. In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or a diluent in an amount of, e.g., less than about 90% (v/v), less than about 80% (v/v), less than about 70% (v/v), less than about 65% (v/v), less than about 60% (v/v), less than about 55% (v/v), less than about 50% (v/v), less than about 45% (v/v), less than about 40% (v/v), less than about 35% (v/v), less than about 30% (v/v), less than about 25% (v/v), less than about 20% (v/v), less than about 15% (v/v), less than about 10% (v/v), less than about 5% (v/v), or less than about 1 % (v/v). In other aspects of this embodiment, a pharmaceutical composition disclosed herein may comprise a solvent, emulsion or other diluent in an amount in a range of, e.g., about 1% (v/v) to 90% (v/v), about 1 % (v/v) to 70% (v/v), about 1% (v/v) to 60% (v/v), about

1% (v/v) to 50% (v/v), about 1 % (v/v) to 40% (v/v), about 1% (v/v) to 30% (v/v), about

1% (v/v) to 20% (v/v), about 1 % (v/v) to 10% (v/v), about 2% (v/v) to 50% (v/v), about

2% (v/v) to 40% (v/v), about 2% (v/v) to 30% (v/v), about 2% (v/v) to 20% (v/v), about

2% (v/v) to 10% (v/v), about 4% (v/v) to 50% (v/v), about 4% (v/v) to 40% (v/v), about

4% (v/v) to 30% (v/v), about 4% (v/v) to 20% (v/v), about 4% (v/v) to 10% (v/v), about

6% (v/v) to 50% (v/v), about 6% (v/v) to 40% (v/v), about 6% (v/v) to 30% (v/v), about

6% (v/v) to 20% (v/v), about 6% (v/v) to 10% (v/v), about 8% (v/v) to 50% (v/v), about

8% (v/v) to 40% (v/v), about 8% (v/v) to 30% (v/v), about 8% (v/v) to 20% (v/v), about

8% (v/v) to 15% (v/v), or about 8% (v/v) to 12% (v/v).

[00136] The final concentration of a pharmaceutical composition disclosed herein may be of any concentration desired. In an aspect of this embodiment, the final concentration of a pharmaceutical composition disclosed herein may be a therapeutically effective amount. In other aspects of this embodiment, the final concentration of a pharmaceutical composition disclosed herein may be, e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1 ,000 mg/mL, or at least 1 ,200 mg/mL. In other aspects of this embodiment, the concentration of a pharmaceutical composition disclosed herein in the solution may be, e.g., at most 1 ,000 mg/mL, at most 1 ,100 mg/mL, at most 1 ,200 mg/mL, at most 1 ,300 mg/mL, at most 1 ,400 mg/mL, at most 1 ,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other aspects of this embodiment, the final concentration of a pharmaceutical composition disclosed herein may be in a range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1 ,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1 ,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1 ,500 mg/mL, about 250 mg/mL to about 1 ,500 mg/mL, about 500 mg/mL to about 1 ,500 mg/mL, about 750 mg/mL to about 1 ,500 mg/mL, about 1 ,000 mg/mL to about 1 ,500 mg/mL, about 100 mg/mL to about 1 ,200 mg/mL, about 250 mg/mL to about 1 ,200 mg/mL, about 500 mg/mL to about 1 ,200 mg/mL, about 750 mg/mL to about 1 ,200 mg/mL, about 1 ,000 mg/mL to about 1 ,200 mg/mL, about 100 mg/mL to about 1 ,000 mg/mL, about 250 mg/mL to about 1 ,000 mg/mL, about 500 mg/mL to about 1 ,000 mg/mL, about 750 mg/mL to about 1 ,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.

[00137] Similarly, the final concentration of thiamine and/or sulbutiamine in a composition disclosed herein can be of any concentration desired. In an aspect of this embodiment, the final concentration is a therapeutically effective amount. In other aspects of this embodiment, the final concentration of a thiamine and/or sulbutiamine is e.g., at least 0.00001 mg/mL, at least 0.0001 mg/mL, at least 0.001 mg/mL, at least 0.01 mg/mL, at least 0.1 mg/mL, at least 1 mg/mL, at least 10 mg/mL, at least 25 mg/mL, at least 50 mg/mL, at least 100 mg/mL, at least 200 mg/mL, at least 500 mg/mL, at least 700 mg/mL, at least 1 ,000 mg/mL, or at least 1 ,200 mg/mL. In other aspects of this embodiment, the concentration can be, e.g., at most 1 ,000 mg/mL, at most 1 ,100 mg/mL, at most 1 ,200 mg/mL, at most 1 ,300 mg/mL, at most 1 ,400 mg/mL, at most 1 ,500 mg/mL, at most 2,000 mg/mL, at most 2,000 mg/mL, or at most 3,000 mg/mL. In other aspects of this embodiment, the final concentration of a pharmaceutical composition disclosed herein may be in a range of, e.g., about 0.00001 mg/mL to about 3,000 mg/mL, about 0.0001 mg/mL to about 3,000 mg/mL, about 0.01 mg/mL to about 3,000 mg/mL, about 0.1 mg/mL to about 3,000 mg/mL, about 1 mg/mL to about 3,000 mg/mL, about 250 mg/mL to about 3,000 mg/mL, about 500 mg/mL to about 3,000 mg/mL, about 750 mg/mL to about 3,000 mg/mL, about 1 ,000 mg/mL to about 3,000 mg/mL, about 100 mg/mL to about 2,000 mg/mL, about 250 mg/mL to about 2,000 mg/mL, about 500 mg/mL to about 2,000 mg/mL, about 750 mg/mL to about 2,000 mg/mL, about 1 ,000 mg/mL to about 2,000 mg/mL, about 100 mg/mL to about 1 ,500 mg/mL, about 250 mg/mL to about 1 ,500 mg/mL, about 500 mg/mL to about 1 ,500 mg/mL, about 750 mg/mL to about 1 ,500 mg/mL, about 1 ,000 mg/mL to about 1 ,500 mg/mL, about 100 mg/mL to about

1 ,200 mg/mL, about 250 mg/mL to about 1 ,200 mg/mL, about 500 mg/mL to about

1 ,200 mg/mL, about 750 mg/mL to about 1 ,200 mg/mL, about 1 ,000 mg/mL to about

1 ,200 mg/mL, about 100 mg/mL to about 1 ,000 mg/mL, about 250 mg/mL to about 1 ,000 mg/mL, about 500 mg/mL to about 1 ,000 mg/mL, about 750 mg/mL to about 1 ,000 mg/mL, about 100 mg/mL to about 750 mg/mL, about 250 mg/mL to about 750 mg/mL, about 500 mg/mL to about 750 mg/mL, about 100 mg/mL to about 500 mg/mL, about 250 mg/mL to about 500 mg/mL, about 0.00001 mg/mL to about 0.0001 mg/mL, about 0.00001 mg/mL to about 0.001 mg/mL, about 0.00001 mg/mL to about 0.01 mg/mL, about 0.00001 mg/mL to about 0.1 mg/mL, about 0.00001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 0.01 mg/mL, about 0.001 mg/mL to about 0.1 mg/mL, about 0.001 mg/mL to about 1 mg/mL, about 0.001 mg/mL to about 10 mg/mL, or about 0.001 mg/mL to about 100 mg/mL.

[00138] Aspects of the present specification disclose, in part, treating an individual suffering from addiction. As used herein, the term "treating," refers to reducing or eliminating in an individual a symptom of addiction; or delaying or preventing relapse in an individual. For example, the term "treating" can mean reducing a symptom (e.g., craving and/or physiological dependence) by, e.g., at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% at least 95%, or at least 100%. The actual symptoms associated with addiction are well known and can be determined by a person of ordinary skill in the art by taking into account factors including, without limitation, the type of addiction, the severity, and/or the tissue or organs affected by the addiction. Those skilled in the art will know the appropriate symptoms or indicators associated with a specific type of addiction and will know how to determine if an individual is a candidate for treatment as disclosed herein. [00139] In another aspect, a pharmaceutical composition disclosed herein reduces the severity of a symptom of a disorder associated with addiction. In aspects of this embodiment, a pharmaceutical composition disclosed herein reduces the severity of a symptom of a disorder associated with addiction by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95%. In other aspects of this embodiment, a pharmaceutical composition disclosed herein reduces the severity of a symptom of a disorder associated with addiction by, e.g., about 10% to about 100%, about 20% to about 100%, about 30% to about 100%, about 40% to about 100%, about 50% to about 100%, about 60% to about 100%, about 70% to about 100%, about 80% to about 100%, about 10% to about 90%, about 20% to about 90%, about 30% to about 90%, about 40% to about 90%, about 50% to about 90%, about 60% to about 90%, about 70% to about 90%, about 10% to about 80%, about 20% to about 80%, about 30% to about 80%, about 40% to about 80%, about 50% to about 80%, or about 60% to about 80%, about 10% to about 70%, about 20% to about 70%, about 30% to about 70%, about 40% to about 70%, or about 50% to about 70%.

[00140] In aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with addiction by, e.g., at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 100%. In other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with addiction by, e.g., at most 10%, at most 15%, at most 20%, at most 25%, at most 30%, at most 35%, at most 40%, at most 45%, at most 50%, at most 55%, at most 60%, at most 65%, at most 70%, at most 75%, at most 80%, at most 85%, at most 90%, at most 95% or at most 100%. In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein reduces a symptom associated with cancer by, e.g., about 10% to about 100%, about 10% to about 90%, about 10% to about 80%, about 10% to about 70%, about 10% to about 60%, about 10% to about 50%, about 10% to about 40%, about 20% to about 100%, about 20% to about 90%, about 20% to about 80%, about 20% to about 20%, about 20% to about 60%, about 20% to about 50%, about 20% to about 40%, about 30% to about 100%, about 30% to about 90%, about 30% to about 80%, about 30% to about 70%, about 30% to about 60%, or about 30% to about 50%.

[00141] In yet other aspects of this embodiment, a therapeutically effective amount of a pharmaceutical composition disclosed herein generally is in the range of about 0.001 mg/kg/day to about 100 mg/kg/day. In aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be, e.g., at least 0.001 mg/kg/day, at least 0.01 mg/kg/day, at least 0.1 mg/kg/day, at least 1.0 mg/kg/day, at least 5.0 mg/kg/day, at least 10 mg/kg/day, at least 15 mg/kg/day, at least 20 mg/kg/day, at least 25 mg/kg/day, at least 30 mg/kg/day, at least 35 mg/kg/day, at least 40 mg/kg/day, at least 45 mg/kg/day, or at least 50 mg/kg/day. In other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.001 mg/kg/day to about 10 mg/kg/day, about 0.001 mg/kg/day to about 15 mg/kg/day, about 0.001 mg/kg/day to about 20 mg/kg/day, about 0.001 mg/kg/day to about 25 mg/kg/day, about 0.001 mg/kg/day to about 30 mg/kg/day, about 0.001 mg/kg/day to about 35 mg/kg/day, about 0.001 mg/kg/day to about 40 mg/kg/day, about 0.001 mg/kg/day to about 45 mg/kg/day, about 0.001 mg/kg/day to about 50 mg/kg/day, about 0.001 mg/kg/day to about 75 mg/kg/day, or about 0.001 mg/kg/day to about 100 mg/kg/day. In yet other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.01 mg/kg/day to about 10 mg/kg/day, about 0.01 mg/kg/day to about 15 mg/kg/day, about 0.01 mg/kg/day to about 20 mg/kg/day, about 0.01 mg/kg/day to about 25 mg/kg/day, about 0.01 mg/kg/day to about 30 mg/kg/day, about 0.01 mg/kg/day to about 35 mg/kg/day, about 0.01 mg/kg/day to about 40 mg/kg/day, about 0.01 mg/kg/day to about 45 mg/kg/day, about 0.01 mg/kg/day to about 50 mg/kg/day, about 0.01 mg/kg/day to about 75 mg/kg/day, or about 0.01 mg/kg/day to about 100 mg/kg/day. In still other aspects of this embodiment, an effective amount of a pharmaceutical composition disclosed herein may be in the range of, e.g., about 0.1 mg/kg/day to about 10 mg/kg/day, about 0.1 mg/kg/day to about 15 mg/kg/day, about 0.1 mg/kg/day to about 20 mg/kg/day, about 0.1 mg/kg/day to about 25 mg/kg/day, about 0.1 mg/kg/day to about 30 mg/kg/day, about 0.1 mg/kg/day to about 35 mg/kg/day, about 0.1 mg/kg/day to about 40 mg/kg/day, about 0.1 mg/kg/day to about 45 mg/kg/day, about 0.1 mg/kg/day to about 50 mg/kg/day, about 0.1 mg/kg/day to about 75 mg/kg/day, or about 0.1 mg/kg/day to about 100 mg/kg/day.

[00142] Dosing can be single dosage or cumulative (serial dosing), and can be readily determined by one skilled in the art. For instance, treatment of a cancer may comprise a one-time administration of an effective dose of a pharmaceutical composition disclosed herein. Alternatively, treatment of a cancer may comprise multiple administrations of an effective dose of a pharmaceutical composition carried out over a range of time periods, such as, e.g., once daily, twice daily, trice daily, once every few days, or once weekly. The timing of administration can vary from individual to individual, depending upon such factors as the severity of an individual's symptoms. For example, an effective dose of a pharmaceutical composition disclosed herein can be administered to an individual once daily for an indefinite period of time, or until the individual no longer requires therapy. A person of ordinary skill in the art will recognize that the condition of the individual can be monitored throughout the course of treatment and that the effective amount of a pharmaceutical composition disclosed herein that is administered can be adjusted accordingly.

[00143] In embodiments, the prodrugs can cross the blood-brain barrier. In some embodiments, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% of the prodrug crosses the blood brain barrier.

[00144] In embodiments, the prodrugs increase the half-life of a small molecule active agent that is administered to a subject. In some embodiments, the half-life is increased by at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90% or at least 95% compared to a non-conjugated active agent.

[00145] As described above, if desired, other therapeutic agents can be employed in conjunction with those provided in the above-described compositions. The amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.

[00146] It is understood that a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration. One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.

[00147] Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.

[00148] If desired, other therapeutic agents can be employed in conjunction with those provided in the above-described compositions. The amount of active ingredients that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated, the nature of the disease, disorder, or condition, and the nature of the active ingredients.

[00149] It is understood that a specific dose level for any particular patient will vary depending upon a variety of factors, including the activity of the specific active agent; the age, body weight, general health, sex and diet of the patient; the time of administration; the rate of excretion; possible drug combinations; the severity of the particular condition being treated; the area to be treated and the form of administration. One of ordinary skill in the art would appreciate the variability of such factors and would be able to establish specific dose levels using no more than routine experimentation.

[00150] Pharmacokinetic parameters such as bioavailability, absorption rate constant, apparent volume of distribution, unbound fraction, total clearance, fraction excreted unchanged, first-pass metabolism, elimination rate constant, half-life, and mean residence time can be determined by methods well known in the art.

EXAMPLES

[00151] The following non-limiting examples are provided for illustrative purposes only in order to facilitate a more complete understanding of representative embodiments now contemplated. These examples are intended to be a mere subset of all possible contexts in which the components of the formulation may be combined. Thus, these examples should not be construed to limit any of the embodiments described in the present specification, including those pertaining to the type and amounts of components of the formulation and/or methods and uses thereof.

Example 1

Discovery of Compound D3

[00152] During an initial study of addiction therapeutics, a series therapeutic targets were identified from omic data. The data included genomic, transcriptomic, and proteomic dataset comparisons between normal and postmortem brain tissues harvested from human patients addicted to opioids. Using this information, biomolecular targets were identified, and molecules with a specific targeting characteristics were identified. Using this data set, lead compounds were generated in silico and screened for desirable targeting as well as off- target effects, ADME and potential toxicity. [00153] Several selective HT2A and HT6A agonists were identified (FIG. 1). The molecules demonstrated capability of crossing the blood brain barrier. The studies also identified the need for brain-available thiamine as a co-factor. Validation studies followed.

Compound D3

[00154] Compound D3 was identified as having an appropriate Al targeting profile (i.e., an agonist of both HT2A and HTe). Compound D3 was prepared as a salt, and formulated as a DMSO, Tween 80, PBS mixture and dosed IP (via intraperitoneal injection) to rats at 25, 50 or 70 mg/Kg daily. One group received only D3; a second group received D3 and sulbutiamine; a control group received only sulbutiamine.

[00155] The study showed that compound D3 reduced self-administration of fentanyl in rats when combined with sulbutiamine compared to controls. Further, selfadministration of sulbutiamine was protective for over-administration of compound D3. At the highest doses observed, the subjects did not show diminished activity which would suggest psychedelic activity and/or other physiological adverse events. Table 2 below compares attributes of D3 to published compounds with structural similarities.

Example 2

Method of Synthesis of Compound D3 [00156] Compound D3, along with the compounds and analogs disclosed herein can be prepared according to established methodology in the art of organic synthesis. General methods of synthesizing the compound can be found in, e.g., Stuart Warren and Paul Wyatt, Workbook for Organic Synthesis: The Disconnection Approach, second Edition, Wiley, 2010. The compounds also include pharmaceutically acceptable salts thereof, prodrugs thereof, hydrates thereof, solvates thereof and polymorphic crystals thereof. The compounds can be administered as pharmaceutical compositions.

Example 3

Evaluation of Compound D3 to Treat Addiction

[00157] Two of the fundamental features of drug addiction in humans (i.e., loss of control over use and the resulting excessive or compulsive use of the drug) have been modeled in animals using several different methods. A simple method of evaluating acquisition is to give an animal (i.e., rat) access to a drug during a daily experimental session, with deliveries available contingent upon an operant response (that is, lever press). Accordingly, this example relates to animal models effective for studying addiction. Recent studies have demonstrated that rodent models can simulate substance abuse and addiction. See, for example, Linch et al. Comparative Medicine (2010) Vol. 60, No. 3.

[00158] Rats are subject to rodent intravenous drug self- administration paradigm. Specifically, rats are implanted with chronic, indwelling catheters in the jugular vein. The catheter exits the rat on the dorsum, where it is connected to a tether-and-tubing system that is attached to a drug-loaded syringe. Responding on the active lever leads to infusions of the drug.

[00159] Acquisition of drug self-administration then is measured as the number of sessions needed to reach a criterion level of intake, which can be standardized and adjusted for dose and drug availability. The ratio of active to inactive lever press responses is used in conjugation with the intake criteria. All of the study animals are included in the analysis, regardless of whether they acquire self-administration, and the focus is on how rapidly acquisition of self-administration takes place and the percentage of animals in each group that acquire drug self-administration.

[00160] As noted above, rats are exposed to an opioid drug. Two populations of rats are exposed: a first population is then treated with compound D3 + sulbutiamine and a second population (i.e. , control) is left untreated or injected with sulbutiamine alone. The treated population of rats is compared with the control group. Specifically, the ratio of active to inactive lever press responses is compared between the populations. The results demonstrate lower rates of level press responses in rats treated with compound D3 + sulbutiamine. The results indicate that compound D3 (or analog) prevents addiction and/or aid in recovery from addiction.

Example 4

Use of Compound D3 to Treat Addiction

[00161] In this example, a patient suffers from addiction to fentanyl. The patient has used the drug daily and displays a physical dependence to the drug. Conventional methods of treating her addiction have been ineffective. A health care provider suggests use of the compound of D3 along with sulbutiamine.

[00162] Treatment with sulbutiamine can result in lower absorption of the drug described into the brain. As a result, co-administration of the drug with a thiamine equivalent can produce an improved safety profile.

[00163] The formulation is provided in solution for injection. The patient is administered a single dose of the formulation. She undergoes bi-weekly addiction counseling and returns to the clinic for weekly injections.

[00164] In this example, the patient’s symptoms of withdrawal and cravings are reduced approximately 90% after the first injection. She is successful and remains “clean” for three months, after which, she continues bi-weekly counseling without injections. [00165] Embodiments also include a compound for formula GATC-102, GATC-105, GATC-107, GATC-110, GATC-111 , GATC-113, GATC-115, GATC-116, GATC- 120, GATC-121 , GATC-001 , GATC-002, GATC-003, GATC-004, GATC-005, GATC-007, GATC-008, GATC-009, GATC-012, GATC-018, GATC-020, GATC- 021 , GATC-022, GATC-022-P1 , GATC-022-P2, GATC-024, GATC-026, GATC-033, GATC-042, GATC-046, GATC-047, GATC-049, GATC-050, GATC-051 , GATC-054, GATC-055, GATC-056, GATC-062, GATC-064, GATC-067, GATC-068, GATC-073, GATC-074, GATC-075, GATC-076, GATC-077, GATC-078, GATC-079, GATC-080, GATC-081, GATC-083, GATC-084, GATC-085, GATC-088, GATC-089, GATC-090, GATC-093, GATC-096, GATC-098, GATC-100, GATC-103, GATC-104, GATC-111 , GATC-112, GATC-113, GATC-114, GATC-115, GATC-117, GATC-122, GATC-123, GATC-124, GATC-125, GATC-126, GATC-127, GATC-128, GATC-049-P1 , GATC- 049-P2, GATC-067-P1 , GATC-067-P2 or a salt or analog thereof.

[00166] Certain embodiments of the present invention are described herein, including the best mode known to the inventors for carrying out the invention. Of course, variations on these described embodiments will become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventors intend for the present invention to be practiced otherwise than specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law.

Moreover, any combination of the above-described embodiments in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.

[00167] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[00168] Unless otherwise indicated, all numbers expressing a characteristic, item, quantity, parameter, property, term, and so forth used in the present specification and claims are to be understood as being modified in all instances by the term “about.” As used herein, the term “about” means that the characteristic, item, quantity, parameter, property, or term so qualified encompasses a range of plus or minus ten percent above and below the value of the stated characteristic, item, quantity, parameter, property, or term. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the specification and attached claims are approximations that may vary. At the very least, and not as an attempt to limit the application of the doctrine of equivalents to the scope of the claims, each numerical indication should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and values setting forth the broad scope of the invention are approximations, the numerical ranges and values set forth in the specific examples are reported as precisely as possible. Any numerical range or value, however, inherently contains certain errors necessarily resulting from the standard deviation found in their respective testing measurements. Recitation of numerical ranges of values herein is merely intended to serve as a shorthand method of referring individually to each separate numerical value falling within the range. Unless otherwise indicated herein, each individual value of a numerical range is incorporated into the present specification as if it were individually recited herein.

[00169] Specific embodiments disclosed herein may be further limited in the claims using consisting of or consisting essentially of language. When used in the claims, whether as filed or added per amendment, the transition term “consisting of” excludes any element, step, or ingredient not specified in the claims. The transition term “consisting essentially of” limits the scope of a claim to the specified materials or steps and those that do not materially affect the basic and novel characteristic(s). Embodiments of the present invention so claimed are inherently or expressly described and enabled herein. [00170] Groupings of alternative embodiments, elements, or steps of the present invention are not to be construed as limitations. Each group member may be referred to and claimed individually or in any combination with other group members disclosed herein. It is anticipated that one or more members of a group may be included in, or deleted from, a group for reasons of convenience and/or patentability. When any such inclusion or deletion occurs, the specification is deemed to contain the group as modified thus fulfilling the written description of all Markush groups used in the appended claims.

[00171] All patents, patent publications, and other publications referenced and identified in the present specification are individually and expressly incorporated herein by reference in their entirety for the purpose of describing and disclosing, for example, the compositions and methodologies described in such publications that might be used in connection with the present invention. These publications are provided solely for their disclosure prior to the filing date of the present application. Nothing in this regard should be construed as an admission that the inventors are not entitled to antedate such disclosure by virtue of prior invention or for any other reason. All statements as to the date or representation as to the contents of these documents is based on the information available to the applicants and does not constitute any admission as to the correctness of the dates or contents of these documents.

[00172] In closing, it is to be understood that although aspects of the present specification are highlighted by referring to specific embodiments, one skilled in the art will readily appreciate that these disclosed embodiments are only illustrative of the principles of the subject matter disclosed herein. Therefore, it should be understood that the disclosed subject matter is in no way limited to a particular methodology, protocol, and/or reagent, etc., described herein. As such, various modifications or changes to or alternative configurations of the disclosed subject matter can be made in accordance with the teachings herein without departing from the spirit of the present specification. Lastly, the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention, which is defined solely by the claims. Accordingly, the present invention is not limited to that precisely as shown and described.

Claims

CLAIMS What is claimed is:

1. A compound of formula GATC-102, GATC-105, GATC-107, GATC-110, GATC-111 , GATC-113, GATC-115, GATC-116, GATC-120, GATC-121 , GATC-001 , GATC-002, GATC-003, GATC-004, GATC-005, GATC-007, GATC-008, GATC- 009, GATC-012, GATC-018, GATC-020, GATC-021 , GATC-022, GATC-022-P1 , GATC-022-P2, GATC-024, GATC-026, GATC-033, GATC-042, GATC-046, GATC- 047, GATC-049, GATC-050, GATC-051 , GATC-054, GATC-055, GATC-056, GATC- 062, GATC-064, GATC-067, GATC-068, GATC-073, GATC-074, GATC-075, GATC- 076, GATC-077, GATC-078, GATC-079, GATC-080, GATC-081 , GATC-083, GATC- 084, GATC-085, GATC-088, GATC-089, GATC-090, GATC-093, GATC-096, GATC- 098, GATC-100, GATC-103, GATC-104, GATC-111 , GATC-112, GATC-113, GATC- 114, GATC-115, GATC-117, GATC-122, GATC-123, GATC-124, GATC-125, GATC- 126, GATC-127, GATC-128, GATC-049-P1 , GATC-049-P2, GATC-067-P1 , GATC- 067-P2 or a salt or analog thereof.

2. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 and a pharmaceutically acceptable carrier.

3. A method of treating addiction and/or reducing relapse use of an addictive agent in a subject, the method comprised of administering an effective amount of a compound of claim 1 to the subject.

4. The method of claim 3, further comprised of administering an effective amount of thiamine to the subject.

5. The method of claim 3, further comprised of administering an effective amount of sulbutiamine to the subject.

6. The method of claim 3, wherein the addictive agent is selected from alcohol, nicotine, marijuana, a marijuana derivative, an opioid agonist, a benzodiazepine, a barbiturate, and a psychostimulant.

7. The method of claim 6, wherein the opioid agonist is selected from morphine, methadone, fentanyl, sufentanil, and heroin.

8. The method of claim 6, wherein the opioid agonist is oxycodone or hydrocodone.

9. The method of claim 6, wherein the psychostimulant is cocaine, amphetamine, or an amphetamine derivative.

10. The method of claim 6, wherein the psychostimulant is cocaine.

11. A method of treating an ailment in a subject, the method comprised of administering an effective amount of a compound of claim 1 to the subject.

12. The method of claim 11 , further comprised of administering an effective amount of thiamine to the subject.

13. The method of claim 11 , further comprised of administering an effective amount of sulbutiamine other thiamine derivative to the subject.

14. The method of claim 11 , wherein the ailment is associated with 5-HT2A receptor activity and/or 5-HTe receptor activity.

15. The method of claim 11 , wherein the ailment is anxiety, inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, depression, Parkinson's disease, stroke, headaches, encephalitis, myasthenia gravis, depression, headaches (e.g., migraines), glaucoma, insomnia, fibromyalgia, a mood disorder (e.g., bipolar), epilepsy, anxiety and/or obsessive-compulsive disorder (OCD).

16. A method of improving neural function in a subject, the method comprised of administering an effective amount of a compound of claim 1 to the subject.

17. The method of claim 16, further comprised of administering an effective amount of thiamine to the subject.

18. The method of claim 16, further comprised of administering an effective amount of sulbutiamine or other thiamine derivative to the subject.

19. A method promoting neuroplasticity in a subject, the method comprised of administering an effective amount of a compound of claim 1 to the subject.

20. The method of claim 19, further comprised of administering an effective amount of thiamine to the subject.

21. The method of claim 19, further comprised of administering an effective amount of sulbutiamine to the subject.

22. A method promoting neuroplasticity in a subject, the method comprised of administering an effective amount of a compound of claim 1 to the subject.

23. The method of claim 19, further comprised of administering an effective amount of thiamine to the subject.

24. The method of claim 19, further comprised of administering an effective amount of sulbutiamine to the subject.

25. A compound of formula D3, a salt or analog thereof:

Formula D3.

26. A pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 25 and a pharmaceutically acceptable carrier.

27. A method of treating addiction and/or reducing relapse use of an addictive agent in a subject, the method comprised of administering an effective amount of a compound of formula D3 to the subject.

28. The method of claim 27, further comprised of administering an effective amount of thiamine to the subject.

29. The method of claim 27, further comprised of administering an effective amount of sulbutiamine to the subject.

30. The method of claim 27, wherein the addictive agent is selected from alcohol, nicotine, marijuana, a marijuana derivative, an opioid agonist, a benzodiazepine, a barbiturate and a psychostimulant.

31. The method of claim 30, wherein the opioid agonist is selected from morphine, methadone, fentanyl, sufentanil, and heroin.

32. The method of claim 30, wherein the opioid agonist is oxycodone or hydrocodone.

33. The method of claim 30, wherein the psychostimulant is cocaine, amphetamine, or an amphetamine derivative.

34. The method of claim 30, wherein the psychostimulant is cocaine.

35. A method of treating an ailment in a subject, the method comprised of administering an effective amount of a compound of formula D3 to the subject.

36. The method of claim 35, further comprised of administering an effective amount of thiamine to the subject.

37. The method of claim 35, further comprised of administering an effective amount of sulbutiamine to the subject.

38. The method of claim 35, wherein the ailment is associated with 5-HT2A receptor activity and/or 5-HTe receptor activity.

39. The method of claim 35, wherein the ailment is anxiety, inflammation, addiction, post-traumatic stress disorder (PTSD), traumatic brain injury, depression, acute spinal cord injury, Alzheimer's disease, Amyotrophic Lateral Sclerosis (ALS), ataxia, Bell's Palsy, brain tumors, cerebral aneurysm, epilepsy and seizures, Guillain-Barre Syndrome, headache, head injury, hydrocephalus, meningitis, multiple sclerosis, muscular dystrophy, neurocutaneous syndromes, depression, Parkinson's disease, stroke, headaches, encephalitis, myasthenia gravis, depression, headaches (e.g., migraines), glaucoma, insomnia, fibromyalgia, a mood disorder (e.g., bipolar), epilepsy, anxiety and/or obsessive-compulsive disorder (OCD).