Pharmaceutical compounds for treatment of bipolar disorder

Abstract

Compounds having a 3,4,6-substituted benzocyclobuten-1-yl-methylamine structure, pharmaceutical compositions and methods employing use thereof for treating acute or chronic bipolar disorders, neuropsychiatric disorders, neurodegenerative conditions and other health conditions associated with neuronal excitability or dysregulated synaptic neurotransmission. The disclosed compounds selectively and rapidly reduce the frequency of action potentials in cortical pyramidal neurons by modulating presynaptic glutamate release while preserving GABAergic neurotransmission and single action potential properties. Selective modulation of excitatory neurotransmission achieves rapid therapeutic effects within minutes to hours after ingestion without disrupting inhibitory transmission, presenting a therapeutic approach for neurological conditions characterized by neuronal hyperexcitability and other pathological excitatory-inhibitory neurotransmission imbalance.

Description

PHARMACEUTICAL COMPOUNDS FOR TREATMENT OF BIPOLAR DISORDERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This Patent Application claims priority from United States Provisional Patent Application No. 63 / 562,675, filed March 7, 2024 and entitled PHARMACEUTICAL COMPOUNDS FOR TREATMENT OF BIPOLAR DISORDER, the entirety of which is hereby incorporated by reference.FIELD

[0002] The present disclosure relates to pharmaceutical compounds for treatment of bipolar disorder.BACKGROUND

[0003] Bipolar disorder is a severe and disabling neuropsychiatric disorder characterized by recurrent episodes of mania or hypomania and depression. It is associated with an elevated risk of suicide and comorbidities including metabolic syndrome, diabetes mellitus, osteoporosis, fibromyalgia, and other endocrine, cardiovascular, and psychiatric disorders.

[0004] With a lifetime prevalence estimate of 1 to 4 %, bipolar disorder is a common neuropsychiatric disorder representing one of the leading causes of disability worldwide due to its impact on patients, their families, and society.

[0005] Bipolar disorder is typically diagnosed during adolescence or early adult and is based on the self-reported experiences of the individual and or by the observations of abnormal behavior by friends, family members, and health care professionals. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (the “DSM-5”) classifies bipolar disorder into several subtypes that include Bipolar I, Bipolar II, Cyclothymic Disorder, and residual categories of atypical forms that do not fit in the abovementioned subtypes. The subclassification of bipolar disorder depends on the severity and duration of manic (or hypomanic) and depressive episodes.

[0006] The etiology of bipolar disorder is complex and multifactorial, with genetic and environmental factors contributing to its development. The heritability of bipolardisorder is estimated to be as high as 85%, among the highest estimates for any psychiatric disorder. While numerous genetic variants have been associated with the risk of bipolar disorder, much remains to be known about the mechanisms underlying its etiology. The role of environmental factors is also unclear, but evidence suggests that perinatal factors, life events, and drug misuse are potential risk factors.

[0007] Bipolar disorder is a chronic and recurrent disorder that is managed with a combination of pharmacotherapy, psychotherapy, and lifestyle interventions. Mood stabilizers (e.g., lithium carbonate), antipsychotics (e.g., lurasidone), and off-label medications are commonly used for the treatment of acute episodes and for maintenance therapy to decrease the risk of relapse. However, existing medications benefit only a subset of patients, metabolic risks are substantial, and rates of discontinuation are high. Psychotherapy can also help to manage symptoms and provide support for the patient. Lifestyle changes such as maintaining a regular sleep schedule, avoiding drugs and alcohol, and engaging in healthy activities can also be beneficial.

[0008] Current therapeutics for bipolar disorder apply a generalized approach, often resulting in suboptimal patient outcomes and high incidence of adverse effects. Current therapeutics include mood stabilizers, antipsychotics and antidepressants, and fail to address molecular heterogeneity inherent in bipolar disorder. This homogenous approach results in failure of the treatment on individual patient profiles. Long-term use of many pharmaceutical treatments for bipolar disorder is frequently associated with significant side effects and variable efficacy, exacerbating the burden on patients. The clinical landscape underscores a critical unmet need for innovative, precision-based therapies that can provide more targeted, effective, and safer treatment options.SUMMARY

[0009] In view of shortcomings of previous approaches to treatment of bipolar disorder, there is motivation to provide alternative pharmaceutical interventions with improved safety, greater efficacy, more rapid onset time or other improved features.

[0010] Generally, the present disclosure provides pharmaceutical compositions for mitigation of symptoms or other treatment of physiological, psychological, or other physical health or mental health conditions. The pharmaceutical compositions disclosedherein may be applied to health conditions characterized by neuronal excitability due to elevated glutamatergic neurotransmission, decreased gamma-amino-butyric acid (“GABA”) mediated inhibitory neurotransmission, referred to as GABAergic neurotransmission, or both. The pharmaceutical compositions disclosed herein demonstrate an acute decrease in presynaptic glutamate release in neocortical layer ll / lll pyramidal neurons without statistically significant effects on GABAergic neurotransmission, allowing modulation of neuronal hyperexcitability through targeted correction of excitatory / inhibitory balance in cortical circuits.

[0011] The pharmaceutical compositions may be applied to mitigation of symptoms or other treatment of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. In particular, bipolar disorder, such as bipolar 1 , bipolar 2 and cyclothymic disorder, may be treated through acute application of the pharmaceutical compositions described herein. Decreasing glutamate release without effecting GABAergic neurotransmission may also mitigate side effects associated with lithium carbonate or other medications increasing GABAergic neurotransmission. Such side effects may include cognitive impairment, sedation, tremors, and emotional blunting.

[0012] The pharmaceutical compositions described herein may be formulated into pharmaceutical drug products in various dosage forms, including oral, injectable, transdermal, sublingual, or other suitable formulations designed to achieve the desired therapeutic outcome. The formulation may incorporate excipients, carriers, or other components to enhance stability, bioavailability, or patient compliance. The pharmaceutical drug product may be used alone or in combination with other therapeutic agents, lifestyle modifications, or adjunct treatments as part of a comprehensive management plan for bipolar disorder.

[0013] Some embodiments of the pharmaceutical compositions include the compound 4-bromo-3,6-dimethoxybenzocyclobuten-1 -yl-methylamine, also called “2C- BCB” or “TCB-2”, or analogues of TCB-2. Changes in transcriptom ic signalling inducedby TCB-2 are predictive of reversing complex transcriptom ic alterations associated with bipolar disorder, as identified in analysis of transcriptional data from postmortem human biological samples from individuals diagnosed with bipolar disorder. Based on the analysis of transcriptional data, application of TCB-2 may restore a transcriptional state akin to that observed in individuals unaffected by bipolar disorder. Whole cell patchclamp electrophysiology confirms acute TCB-2 application to layer ll / lll cortical brain slices diminishes neuronal hyperexcitability in a genetically validated mutant mouse model of bipolar disorder (Ank3 p.W1989R). The results of the patch-clamp electrophysiology experiments following minutes of exposure to TCB-2 align directionally with outcomes observed after several weeks of chronic in vivo lithium carbonate treatment.

[0014] Structure (I) shows the structure of benzocyclobutane compounds, or more specifically benzocyclobutylmethylamine compounds, of which TCB-2 is an example:

[0015] In structure (I), R1 and R3 may each be -CH3, -CH2CH3, -CH(CH3)2, or - CH2CH2CH3, respectively providing methoxy, ethoxy, isopropyloxy, n-propyloxy functional groups. R1 and R3 may be the same substituent or different substituents. In structure (I), R2 may include Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl or thio-n-propyl.

[0016] The structure of TCB-2 is shown in structure (II), where, relative to structure (I), R1 and R3 are each -CH3, providing methoxy groups at positions 6 and 3, respectively, and R2 is Br:

[0017] TCB-2 is a benzocyclobutylmethylamine with similar ring substitution to phenethylamine and amphetamine psychedelic drugs, with closest comparison to 2C-B and DOB. While there is no clear evidence TCB-2 is a psychoactive compound, typically, schizophrenia, bipolar disorder and certain other mental health conditions are contraindications for therapeutic use of psychedelics. Schizophrenia and bipolar disorder are common exclusion criteria for clinical trials involving psychedelic drugs. Psychedelic drugs generally, including 2C-B and DOB, are often agonists at the 5-HT2A receptor, among other receptors. TCB-2 binds to 5-HT2A, although some effects of TCB-2 in mice persist in the presence of strong 5-HT2A antagonists or in mice lacking 5-HT2A receptors (Fox et al., 2010; Halberstadt et al., 2013). Despite structural similarity to 2C-B and other phenethylamine drugs, there is no clear evidence that TCB-2 is a psychedelic drug in humans.

[0018] Management of bipolar disorder patients typically includes pharmacological treatment, psychotherapy and lifestyle approaches. Existing pharmacological approaches to treatment of bipolar disorder include mood stabilizers (e.g. lithium carbonate, carbamazepine etc.), antipsychotics (e.g. aripiprazole, lurasidone etc.), and off-label use of antidepressants. Nonpharmacological treatments for bipolar depression include electroconvulsive therapy (“ECT”), repetitive transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, lifestyle interventions and psychotherapy.

[0019] The compounds described herein, including TCB-2 and other compounds shown in structure (I), may provide relief from bipolar disorder or other therapeutic benefits to individuals suffering from bipolar disorder. Without being bound by any theory, the compounds may modulate specific genes and signaling pathways involved withvascular function, neuroinflammation, stress response, and metal ion homeostasis that may be dysregulated in patients affected by bipolar disorder. Transcriptom ic data described herein supports modulation by TCB-2 of a transcriptional signature observed in biological samples sourced from individuals affected by bipolar disorder toward a transcriptional signature associated with individuals unaffected by bipolar disorder. Electrophysiology experiments confirm TCB-2 normalizes action potential firing frequency in layer ll / lll cortical pyramidal neurons towards baseline levels, directly linking transcriptional modulation to functional restoration of cortical excitability.

[0020] TCB-2 was assessed for acute effects on electrophysiological properties of excitatory glutamatergic pyramidal neurons in the mouse forebrain. Whole cell voltageclamp recordings from ex vivo slices of mouse neocortex were assessed for single action potential properties, maximum AP firing frequency, sIPSCs, and excitatory postsynaptic currents after bath application of 1 pM TCB-2, application of saline vehicle only, or without administration of any substance.

[0021] As shown in Figs. 1 and 2, electrophysiology data from whole cell patchclamp studies described herein provides evidence the compounds, exemplified by TCB- 2, modulates layer ll / lll cortical pyramidal neuron excitability in cortical slices from each of wild-type mice and Ank3 p.W1989R mice, correcting an inhibitory / excitatory imbalance linked to bipolar disorder and other neuropsychiatric disorders. The electrophysiological data show that TCB-2 rapidly corrects electrophysiological deficits linked to bipolar disorder within minutes of application to cortical brain slices from Ank3 p.W1989R mice, a validated genetic mouse model of bipolar disorder.

[0022] Electrophysiological data following acute exposure to TCB-2 demonstrate a statistically-significant reduction in the firing frequency of layer ll / lll pyramidal neurons from cortical slices of both wild-type and Ank3 p.W1989R mice mice, consistent with human genetic evidence and therapeutic validation studies support targeting dysregulated synaptic neurotransmission for achieving clinical benefit in bipolar disorder and conditions characterized by neuronal hyperexcitability.

[0023] Additional electrophysiological data demonstrate that TCB-2 exposure results in the reduction of neuronal firing frequency through presynaptic modulation of glutamatergic neurotransmission. Exposure to TCB-2 achieves targeted presynapticmodulation of glutamatergic neurotransmission without altering GABAergic inhibitory neurotransmission or modifying fundamental single action potential (“SAP”) properties. This selective mechanism of action provides a neurophysiological basis for rapid onset of effects of TCB-2 observed and reported herein, and the corresponding rapid onset of therapeutic properties of TCB-2 and other compounds within structure (I), and the favorable side effect profile compared with lithium carbonate or other mood stabilizers, including mood stabilizers which attenuate hyperexcitability by eliciting a GABAergic response to increase GABAergic neurotransmission.

[0024] Three key electrophysiological observations from whole-cell patch clamp studies in mouse neocortex layer ll / lll pyramidal neurons support a presynaptic mechanism for reducing firing frequency of layer ll / lll pyramidal cells by TCB-2 and other compounds with structure (I).

[0025] First in both wild-type and Ank3 p.W1989R mice, acute exposure to TCB-2 resulted in a statistically significant reduction in spontaneous excitatory postsynaptic currents (“sEPSCs”) frequency, without affecting sEPSC amplitude. A reduction in sEPSC frequency and corresponding reduction in presynaptic glutamate release may provide a causal mechanistic explanation for the decreased firing frequency. Figs. 3A and 3B show corresponding data for wild-type mice.

[0026] Second, acute exposure to TCB-2 in layer ll / ll cortical pyramidal neurons resulted in no statistically significant change in spontaneous inhibitory postsynaptic currents (“sIPSCs”) frequency or amplitude from either wild-type or Ank3 p.W1989R mice. While Ank3 p.W1989R mice exhibit significantly reduced sIPSC frequency, TCB- 2’s effect on reducing aberrant neuronal firing frequency is not attributable to the rescue of impaired GABAergic neurotransmission. Figs. 4A and 4B show corresponding data for wild-type mice.

[0027] Third, in both wild-type and Ank3 p.W1989R mice, acute exposure to TCB- 2 resulted in no statistically significant change in any SAP properties. The SAP properties measured included resting membrane potential, SAP threshold, SAP amplitude, Rheobase, dv / dt depolarization and dv / dt repolarization. Each of these SAP properties were unaffected, indicating that acute exposure to TCB-2 does not directly affect ionchannels (e.g. voltage gated Na+ / K+channels) underlying these specific suprathreshold parameters in pyramidal neurons.

[0028] The lack of impact on sIPSCs after exposure to TCB-2 suggests TCB-2 and other compounds with structure (I) may function through a mechanism of action for lowering pyramidal cell excitability functions independently of GABAergic neurotransmission, diverging from the GABAergic neurotransmission therapeutic mechanism of action of chronic lithium treatment (Caballero-Floran et al., 2023).

[0029] The rapid onset of TCB-2 contrasts with lithium carbonate. Lithium carbonate rectifies aberrant GABAergic neurotransmission and neuronal excitability in cortical pyramidal neurons only after several weeks of chronic treatment, as demonstrated in similar patch-clamp experiments with lithium carbonate administration (Caballero-Floran et al., 2023). The lack of change in GABAergic neurotransmission associated with TCB-2 suggests side effects, adverse events or other unwanted non- therapeutic physiological effects resulting from increased GABAergic neurotransmission may be mitigated through use of TCB-2 and other compounds with structure (I).

[0030] Some common side effects resulting from chronic use of lithium carbonate, and which may be mitigated through use of TCB-2 and other compounds with structure (I) rather than lithium carbonate, include cognitive impairment, sedation, tremors, and emotional blunting. Each of these side effects may result from, or be exacerbated by, increased GABAergic neurotransmission resulting from use of lithium carbonate. Application of TCB-2 or other compounds with structure (I) for treatment of bipolar disorder may result in mitigation of common side effects and potential adverse events resulting from increased GABAergic neurotransmission may be mitigated in occurrence frequency or intensity, relative to chronic use of lithium.

[0031] Without being bound by any theory, the mechanism of action of TCB-2 and other compounds with structure (I) in correcting neuronal hyperexcitability associated with bipolar disorder, and other conditions, may be primarily based on the G protein-coupled receptor (GPCR)-mediated modulation of presynaptic calcium channels and glutamate release. This potential mechanism of action is consistent with patch clamp data showing, after only eight minutes of TCB-2 exposure to mouse neocortical slices, (a) a statistically- significant reduction of firing frequency in layer ll / lll cortical pyramidal neurons, (b) astatistically-significant reduction of sEPSC frequency without affecting amplitude, (c) no statistically-significant change on sIPSC frequency or amplitude, and (d) no statistically- significant change in single action potential properties. Patch clamp data strongly support a presynaptic mechanism of action effected by TCB-2 and other compounds with structure (I) on pyramidal cell excitability, characterized by selective reduction of presynaptic glutamate release without affecting GABAergic neurotransmission.

[0032] In a first aspect, herein provided are compounds having a 3,4,6-substituted benzocyclobuten-1-yl-methylamine structure, pharmaceutical compositions and methods employing use thereof for treating acute or chronic bipolar disorders, neuropsychiatric disorders, neurodegenerative conditions and other health conditions associated with neuronal excitability or dysregulated synaptic neurotransmission. The disclosed compounds selectively and rapidly reduce the frequency of action potentials in cortical pyramidal neurons by modulating presynaptic glutamate release while preserving GABAergic neurotransmission and single action potential properties. Selective modulation of excitatory neurotransmission achieves rapid therapeutic effects within minutes to hours after ingestion without disrupting inhibitory transmission, presenting a therapeutic approach for neurological conditions characterized by neuronal hyperexcitability and other pathological excitatory-inhibitory neurotransmission imbalance

[0033] In a further aspect, herein provided is a pharmaceutical drug product comprising at least one dosage form, the dosage form comprising a pharmaceutically effective amount of a compound having structure (I):wherein R1 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and - CH2CH2CH3; R2 is selected from the group consisting of Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl, and thio-n-propyl; and R3 is selected from the group consisting of -CH3, - CH2CH3, -CH(CH3)2, and -CH2CH2CH3; or a pharmaceutically acceptable salt thereof; and the dosage form is formulated for the treatment of a health condition associated withone or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission.

[0034] In some embodiments, R1 is -CH3, R2 is Br and R3 is -CH3. In some embodiments, the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. In some embodiments, the health condition is a bipolar disorder. In some embodiments, the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder. In some embodiments, the treatment comprises chronically maintaining relief of at least one symptom of the health condition. In some embodiments, the treatment comprises acute relief from at least one symptom of the health condition. In some embodiments, the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound. In some embodiments, the treatment results in relief within about 4 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 2 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 hour of ingestion of the compound. In some embodiments, the treatment results in relief within about 30 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 15 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 5 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 minute of ingestion of the compound. In some embodiments, the relief is associated with a clinically measurable improvement. In some embodiments, the relief is provided in the context of treatment of the health condition with a separate chronic treatment product. In some embodiments, the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product. In some embodiments, ingestion of the compound results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity ofthe at least one side effect as expected to result from chronic use of lithium carbonate. In some embodiments, the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting. In some embodiments, the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use. In some embodiments, the dosage form includes an amount of the compound of between about 1 pg and about 50 pg. In some embodiments, the dosage form includes an amount of the compound of between about 50 pg and about 100 pg. In some embodiments, the dosage form includes an amount of the compound of between about 100 pg and about 250 pg. In some embodiments, the dosage form includes an amount of the compound of between about 250 pg and about 500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 500 pg and about 800 pg. In some embodiments, the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg. In some embodiments, the dosage form includes an amount of the compound of between about 5 mg and about 10 mg. In some embodiments, the dosage form includes an amount of the compound of between about 10 mg and about 20 mg. In some embodiments, the dosage form includes an amount of the compound of between about 20 mg and about 50 mg. In some embodiments, the dosage form includes an amount of the compound of between about 50 mg and about 100 mg. In some embodiments, the dosage form includes an amount of the compound of between about 100 mg and about 250 mg. In some embodiments, the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir. In some embodiments, the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection. In some embodiments, the dosage form comprisesa dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI). In some embodiments, the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system. In some embodiments, the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency. In some embodiments, ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude. In some embodiments, ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission. In some embodiments, ingestion of the compound results in no statistically significant changes in single action potentials of pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission. In some embodiments, the pharmaceutical drug product includes a label including an indicated use for symptomatic relief or other treatment of the health condition. In some embodiments, the pharmaceutical drug product includes instructions for use of the pharmaceutical drug product in symptomatic relief or other treatment of the health condition, the use including ingestion of the dosage form comprising the pharmaceutically effective amount of the compound. In some embodiments, the pharmaceutical drug product includes a label, and the label includes an indicated use for symptomatic relief or other treatment of the health condition; instructions for use of the pharmaceutical drug product, including by ingestion of the dosage form comprising the pharmaceutically effective amount of the compound. In some embodiments, the pharmaceutical drug product includes a medical device, and wherein the dosage form is incorporated into the medical device for facilitating administration or other ingestion of the dosage form.

[0035] In a further aspect, herein provided is a pharmaceutical drug product comprising at least one dosage form, the dosage form comprising a pharmaceuticallyeffective amount of a compound having structure (II): (II); or a pharmaceutically acceptable salt thereof; and wherein the dosage form is formulated for the treatment of a health condition associated with one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission.

[0036] In some embodiments, the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. In some embodiments, the health condition is a bipolar disorder. In some embodiments, the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder. In some embodiments, the treatment comprises chronically maintaining relief of at least one symptom of the health condition. In some embodiments, the treatment comprises acute relief from at least one symptom of the health condition. In some embodiments, the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound. In some embodiments, the treatment results in relief within about 4 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 2 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 hour of ingestion of the compound. In some embodiments, the treatment results in relief within about 30 minutes of ingestion of the compound. In someembodiments, the treatment results in relief within about 15 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 5 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 minute of ingestion of the compound. In some embodiments, the relief is associated with a clinically measurable improvement. In some embodiments, the relief is provided in the context of treatment of the health condition with a separate chronic treatment product. In some embodiments, the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product. In some embodiments, ingestion of the compound results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate. In some embodiments, the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting. In some embodiments, the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use. In some embodiments, the dosage form includes an amount of the compound of between about 1 pg and about 50 pg. In some embodiments, the dosage form includes an amount of the compound of between about 50 pg and about 100 pg. In some embodiments, the dosage form includes an amount of the compound of between about 100 pg and about 250 pg. In some embodiments, the dosage form includes an amount of the compound of between about 250 pg and about 500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 500 pg and about 800 pg. In some embodiments, the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg. In some embodiments, the dosage form includes an amount of the compound of between about 5 mg and about 10 mg. In some embodiments, the dosage form includes an amount of the compound of between about 10 mg and about 20 mg. In some embodiments, the dosage form includes an amount of the compound of between about 20 mg and about 50 mg. In some embodiments, the dosage form includes an amount of the compound of between about 50 mg and about 100 mg. In some embodiments, the dosage form includes an amount of the compound of between about100 mg and about 250 mg. In some embodiments, the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir. In some embodiments, the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection. In some embodiments, the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI). In some embodiments, the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system. In some embodiments, the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency. In some embodiments, ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude. In some embodiments, ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission. In some embodiments, ingestion of the compound results in no statistically significant changes in single action potentials of pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission. In some embodiments, the pharmaceutical drug product includes a label including an indicated use for symptomatic relief or other treatment of the health condition. In some embodiments, the pharmaceutical drug product includes instructions for use of the pharmaceutical drug product in symptomatic relief or othertreatment of the health condition, the use including ingestion of the dosage form comprising the pharmaceutically effective amount of the compound. In some embodiments, the pharmaceutical drug product includes a label, and the label includes an indicated use for symptomatic relief or other treatment of the health condition; instructions for use of the pharmaceutical drug product, including by ingestion of the dosage form comprising the pharmaceutically effective amount of the compound. In some embodiments, the pharmaceutical drug product includes a medical device, and wherein the dosage form is incorporated into the medical device for facilitating administration or other ingestion of the dosage form.

[0037] In a further aspect, herein provided is a method of treating an individual suffering from a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission, the method comprising: providing a pharmaceutically effective amount of a compound having structure (I); or a pharmaceutically acceptable salt thereof, for ingestion by the individual:wherein R1 is selected from the group consisting of -CH3, -CH2CH3, -CH(CHs)2, and -CH2CH2CH3; R2 is selected from the group consisting of Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl, and thio-n-propyl; and R3 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3.

[0038] In some embodiments, R1 is -CH3, R2 is Br and R3 is -CH3. In some embodiments, the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol usedisorder. In some embodiments, the health condition is a bipolar disorder. In some embodiments, the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder. In some embodiments, providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for chronically maintaining relief of at least one symptom of the health condition. In some embodiments, providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for providing acute relief from at least one symptom of the health condition. In some embodiments, providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for providing relief from at least one symptom of the health condition within the same day as administration of the compound. In some embodiments, the treatment results in relief within about 4 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 2 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 hour of ingestion of the compound. In some embodiments, the treatment results in relief within about 30 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 15 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 5 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 minute of ingestion of the compound. In some embodiments, the relief is associated with a clinically measurable improvement. In some embodiments, the relief is provided in the context of treatment of the health condition with a separate chronic treatment product. In some embodiments, the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product. In some embodiments, ingestion of the compound results in a reduced incidence or seventy of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate. In some embodiments, the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting. In some embodiments, the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use. In some embodiments, the dosage form includes an amount of the compound of between about 1pg and about 50 pg. In some embodiments, the dosage form includes an amount of the compound of between about 50 pg and about 100 pg. In some embodiments, the dosage form includes an amount of the compound of between about 100 pg and about 250 pg. In some embodiments, the dosage form includes an amount of the compound of between about 250 pg and about 500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 500 pg and about 800 pg. In some embodiments, the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg. In some embodiments, the dosage form includes an amount of the compound of between about 5 mg and about 10 mg. In some embodiments, the dosage form includes an amount of the compound of between about 10 mg and about 20 mg. In some embodiments, the dosage form includes an amount of the compound of between about 20 mg and about 50 mg. In some embodiments, the dosage form includes an amount of the compound of between about 50 mg and about 100 mg. In some embodiments, the dosage form includes an amount of the compound of between about 100 mg and about 250 mg. In some embodiments, the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir. In some embodiments, the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection. In some embodiments, the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI). In some embodiments, the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system. In some embodiments, thedosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency. In some embodiments, ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude. In some embodiments, ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission. In some embodiments, ingestion of the compound results in no statistically significant changes in single action potentials of pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

[0039] In a further aspect, herein provided is a method of treating an individual suffering from a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission, the method comprising: providing a pharmaceutically effective amount of a compound having structure (II) ; or a pharmaceutically acceptable salt thereof for ingestion by the individual:

[0040] In some embodiments, the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic braininjury, stroke, and alcohol use disorder. In some embodiments, the health condition is a bipolar disorder. In some embodiments, the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder. In some embodiments, providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for chronically maintaining relief of at least one symptom of the health condition. In some embodiments, providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for providing acute relief from at least one symptom of the health condition. In some embodiments, providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for providing relief from at least one symptom of the health condition within the same day as administration of the compound. In some embodiments, the treatment results in relief within about 4 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 2 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 hour of ingestion of the compound. In some embodiments, the treatment results in relief within about 30 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 15 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 5 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 minute of ingestion of the compound. In some embodiments, the relief is associated with a clinically measurable improvement. In some embodiments, the relief is provided in the context of treatment of the health condition with a separate chronic treatment product. In some embodiments, the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product. In some embodiments, ingestion of the compound results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate. In some embodiments, the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting. In some embodiments, the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use. In some embodiments, the dosage form includes an amount of thecompound of between about 1 pg and about 50 pg. In some embodiments, the dosage form includes an amount of the compound of between about 50 pg and about 100 pg. In some embodiments, the dosage form includes an amount of the compound of between about 100 pg and about 250 pg. In some embodiments, the dosage form includes an amount of the compound of between about 250 pg and about 500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 500 pg and about 800 pg. In some embodiments, the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg. In some embodiments, the dosage form includes an amount of the compound of between about 5 mg and about 10 mg. In some embodiments, the dosage form includes an amount of the compound of between about 10 mg and about 20 mg. In some embodiments, the dosage form includes an amount of the compound of between about 20 mg and about 50 mg. In some embodiments, the dosage form includes an amount of the compound of between about 50 mg and about 100 mg. In some embodiments, the dosage form includes an amount of the compound of between about 100 mg and about 250 mg. In some embodiments, the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir. In some embodiments, the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection. In some embodiments, the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI). In some embodiments, the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and amatrix system. In some embodiments, the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency. In some embodiments, ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude. In some embodiments, ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission. In some embodiments, ingestion of the compound results in no statistically significant changes in single action potentials of pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

[0041] In a further aspect, herein provided is a compound having structure (I):wherein R1 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3; R2 is selected from the group consisting of Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl, and thio-n-propyl; and R3 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3; or a pharmaceutically acceptable salt thereof; for use as a medicament

[0042] In some embodiments, R1 is -CH3, R2 is Br and R3 is -CH3. In some embodiments, the medicament is for treatment of a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission. In some embodiments, the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrumdisorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. In some embodiments, the health condition is a bipolar disorder. In some embodiments, the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder. In some embodiments, the treatment comprises chronically maintenance of relief of at least one symptom of the health condition. In some embodiments, the treatment comprises acute relief from at least one symptom of the health condition. In some embodiments, the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound. In some embodiments, the treatment results in relief within about 4 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 2 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 hour of ingestion of the compound. In some embodiments, the treatment results in relief within about 30 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 15 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 5 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 minute of ingestion of the compound. In some embodiments, the relief is associated with a clinically measurable improvement. In some embodiments, the relief is provided in the context of treatment of the health condition with a separate chronic treatment product. In some embodiments, the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product. In some embodiments, the use as a medicament results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate. In some embodiments, the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting. In some embodiments, the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use. In some embodiments, the dosage form includes an amount of the compound of between about 1 pg and about 50 pg. In some embodiments, the dosageform includes an amount of the compound of between about 50 pg and about 100 pg. In some embodiments, the dosage form includes an amount of the compound of between about 100 pg and about 250 pg. In some embodiments, the dosage form includes an amount of the compound of between about 250 pg and about 500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 500 pg and about 800 pg. In some embodiments, the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg. In some embodiments, the dosage form includes an amount of the compound of between about 5 mg and about 10 mg. In some embodiments, the dosage form includes an amount of the compound of between about 10 mg and about 20 mg. In some embodiments, the dosage form includes an amount of the compound of between about 20 mg and about 50 mg. In some embodiments, the dosage form includes an amount of the compound of between about 50 mg and about 100 mg. In some embodiments, the dosage form includes an amount of the compound of between about 100 mg and about 250 mg. In some embodiments, the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir. In some embodiments, the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection. In some embodiments, the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI). In some embodiments, the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system. In some embodiments, the dosage form further comprises apharmaceutically acceptable carrier, diluent or excipient In some embodiments, the use as a medicament results in a reduction in action potential frequency at pyramidal neurons. In some embodiments, the use as a medicament results in a reduction in glutamatergic neurotransmission frequency. In some embodiments, the use as a medicament results in no statistically significant changes in glutamatergic neurotransmission amplitude. In some embodiments, the use as a medicament results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission. In some embodiments, the use as a medicament results in no statistically significant changes in single action potentials of pyramidal neurons. In some embodiments, the use as a medicament results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

[0043] In a further aspect, herein provided is a compound having structure (II):(II); or a pharmaceutically acceptable salt thereof; for use as a medicament.

[0044] In some embodiments, the medicament is for treatment of a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission. In some embodiments, the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. In some embodiments, the health condition is a bipolar disorder. In some embodiments, the bipolar disorder is selected from the groupconsisting of bipolar 1 , bipolar 2, and cyclothymic disorder. In some embodiments, the treatment comprises chronically maintenance of relief of at least one symptom of the health condition. In some embodiments, the treatment comprises acute relief from at least one symptom of the health condition. In some embodiments, the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound. In some embodiments, the treatment results in relief within about 4 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 2 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 hour of ingestion of the compound. In some embodiments, the treatment results in relief within about 30 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 15 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 5 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 minute of ingestion of the compound. In some embodiments, the relief is associated with a clinically measurable improvement. In some embodiments, the relief is provided in the context of treatment of the health condition with a separate chronic treatment product. In some embodiments, the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product. In some embodiments, the use as a medicament results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate. In some embodiments, the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting. In some embodiments, the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use. In some embodiments, the dosage form includes an amount of the compound of between about 1 pg and about 50 pg. In some embodiments, the dosage form includes an amount of the compound of between about 50 pg and about 100 pg. In some embodiments, the dosage form includes an amount of the compound of between about 100 pg and about 250 pg. In some embodiments, the dosage form includes an amount of the compound of between about 250 pg and about 500 pg. In some embodiments, the dosage form includes an amount of the compound of betweenabout 500 pg and about 800 pg. In some embodiments, the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg. In some embodiments, the dosage form includes an amount of the compound of between about 5 mg and about 10 mg. In some embodiments, the dosage form includes an amount of the compound of between about 10 mg and about 20 mg. In some embodiments, the dosage form includes an amount of the compound of between about 20 mg and about 50 mg. In some embodiments, the dosage form includes an amount of the compound of between about 50 mg and about 100 mg. In some embodiments, the dosage form includes an amount of the compound of between about 100 mg and about 250 mg. In some embodiments, the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir. In some embodiments, the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection. In some embodiments, the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI). In some embodiments, the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system. In some embodiments, the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient In some embodiments, the use as a medicament results in a reduction in action potential frequency at pyramidal neurons. In some embodiments, the use as a medicament results in a reduction in glutamatergic neurotransmission frequency. In some embodiments, the use as a medicament results in no statistically significant changes in glutamatergic neurotransmission amplitude. Insome embodiments, the use as a medicament results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission. In some embodiments, the use as a medicament results in no statistically significant changes in single action potentials of pyramidal neurons. In some embodiments, the use as a medicament results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

[0045] In a further aspect, herein provided is use of a compound having structure (I) in the treatment of an individual suffering from a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission:wherein R1 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3; R2 is selected from the group consisting of Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl, and thio-n-propyl; and R3 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3.

[0046] In some embodiments, R1 is -CH3, R2 is Br and R3 is -CH3. In some embodiments, the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. In some embodiments, the health condition is a bipolar disorder. In some embodiments, the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder. In some embodiments, the treatment comprises chronic maintenance relief of at least one symptom of the health condition. In some embodiments, the treatment comprises acute relief from at least one symptom of thehealth condition. In some embodiments, the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound. In some embodiments, the treatment results in relief within about 4 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 2 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 hour of ingestion of the compound. In some embodiments, the treatment results in relief within about 30 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 15 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 5 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 minute of ingestion of the compound. In some embodiments, the relief is associated with a clinically measurable improvement. In some embodiments, the relief is provided in the context of treatment of the health condition with a separate chronic treatment product. In some embodiments, the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product. In some embodiments, the use results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate. In some embodiments, the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting. In some embodiments, the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use. In some embodiments, the dosage form includes an amount of the compound of between about 1 pg and about 50 pg. In some embodiments, the dosage form includes an amount of the compound of between about 50 pg and about 100 pg. In some embodiments, the dosage form includes an amount of the compound of between about 100 pg and about 250 pg. In some embodiments, the dosage form includes an amount of the compound of between about 250 pg and about 500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 500 pg and about 800 pg. In some embodiments, the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 1 ,500 pg andabout 5 mg. In some embodiments, the dosage form includes an amount of the compound of between about 5 mg and about 10 mg. In some embodiments, the dosage form includes an amount of the compound of between about 10 mg and about 20 mg. In some embodiments, the dosage form includes an amount of the compound of between about 20 mg and about 50 mg. In some embodiments, the dosage form includes an amount of the compound of between about 50 mg and about 100 mg. In some embodiments, the dosage form includes an amount of the compound of between about 100 mg and about 250 mg. In some embodiments, the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir. In some embodiments, the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection. In some embodiments, the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI). In some embodiments, the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system. In some embodiments, the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency. In some embodiments, ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude. In some embodiments, ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission. In some embodiments, ingestion of the compound results in nostatistically significant changes in single action potentials of pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

[0047] In a further aspect, herein provided is use of a compound having structure (II) or a pharmaceutically acceptable sale thereof in the treatment of an individual suffering from a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologicallydecreased GABAergic neurotransmission: (II).

[0048] In some embodiments, the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. In some embodiments, the health condition is a bipolar disorder. In some embodiments, the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder. In some embodiments, the treatment comprises chronic maintenance relief of at least one symptom of the health condition. In some embodiments, the treatment comprises acute relief from at least one symptom of the health condition. In some embodiments, the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound. In some embodiments, the treatment results in relief within about 4 hours of ingestion of the compound. In some embodiments, the treatment results in relief within about 2 hours of ingestion of the compound. In some embodiments, the treatment resultsin relief within about 1 hour of ingestion of the compound. In some embodiments, the treatment results in relief within about 30 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 15 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 5 minutes of ingestion of the compound. In some embodiments, the treatment results in relief within about 1 minute of ingestion of the compound. In some embodiments, the relief is associated with a clinically measurable improvement. In some embodiments, the relief is provided in the context of treatment of the health condition with a separate chronic treatment product. In some embodiments, the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product. In some embodiments, the use results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate. In some embodiments, the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting. In some embodiments, the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use. In some embodiments, the dosage form includes an amount of the compound of between about 1 pg and about 50 pg. In some embodiments, the dosage form includes an amount of the compound of between about 50 pg and about 100 pg. In some embodiments, the dosage form includes an amount of the compound of between about 100 pg and about 250 pg. In some embodiments, the dosage form includes an amount of the compound of between about 250 pg and about 500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 500 pg and about 800 pg. In some embodiments, the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg. In some embodiments, the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg. In some embodiments, the dosage form includes an amount of the compound of between about 5 mg and about 10 mg. In some embodiments, the dosage form includes an amount of the compound of between about 10 mg and about 20 mg. In some embodiments, the dosage form includes an amount of the compound of between about 20 mg and about 50 mg. In some embodiments, the dosage form includes anamount of the compound of between about 50 mg and about 100 mg. In some embodiments, the dosage form includes an amount of the compound of between about 100 mg and about 250 mg. In some embodiments, the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir. In some embodiments, the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection. In some embodiments, the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI). In some embodiments, the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system. In some embodiments, the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency. In some embodiments, ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude. In some embodiments, ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission. In some embodiments, ingestion of the compound results in no statistically significant changes in single action potentials of pyramidal neurons. In some embodiments, ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

[0049] Other aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.BRIEF DESCRIPTION OF THE FIGURES

[0050] Embodiments of the present disclosure will now be described, by way of example only, with reference to the attached Figures.

[0051] Fig. 1 shows a plot of average AP Frequency (Hz) compared with current injection (pA) in cortical pyramidal neurons from Ank3 p.W.1989R mice;

[0052] Fig. 2 shows a plot of average AP Frequency (Hz) compared with current injection (pA) in cortical pyramidal neurons from wild type C57BI6 / J mice;

[0053] Fig. 3A shows a plot of sEPSC frequency in cortical pyramidal neurons from wild type C57BI6 / J mice;

[0054] Fig. 3B shows a plot of sEPSC amplitude in cortical pyramidal neurons from wild type C57BI6 / J mice;

[0055] Fig. 4A shows a plot of sIPSC frequency in cortical pyramidal neurons from wild type C57BI6 / J mice; and

[0056] Fig. 4B shows a plot of sIPSC amplitude in cortical pyramidal neurons from wild type C57BI6 / J mice.DETAILED DESCRIPTION

[0057] Generally, the present disclosure provides pharmaceutical compositions for mitigation of symptoms or other treatment of physiological, psychological, or other physical health or mental health conditions. The pharmaceutical compositions may be applied to mitigation of symptoms or other treatment of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder.

[0058] The pharmaceutical compositions described herein include a compound, which may be applied as an active pharmaceutical ingredient (“API”) to formulate into a dosage form for oral use, parenteral use, inhalation or transdermal use. The compound is a 3,4,6-ring-substituted benzocyclobutylmethylamine as shown in structure (I):

[0059] In structure (I), R1 may be -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2CH3, respectively providing methoxy, ethoxy, isopropyloxy, n-propyloxy functional groups at position 6 of the phenyl ring. In structure (I), R2 may include Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl or thio-n-propyl. In structure (I), R3 may be -CH3, -CH2CH3, -CH(CH3)2, or -CH2CH2CH3, respectively providing methoxy, ethoxy, isopropyloxy, n-propyloxy functional groups at position 3 of the phenyl ring.

[0060] 4-Bromo-3,6-dimethoxybenzocyclobuten-1 -yl-methylamine, also called “2C-BCB” or “TCB-2”, is one example of the compounds which may be used in the pharmaceutical compositions described herein. The structure of TCB-2 is shown in structure (II), where, relative to structure (I), R1 is -CH3, providing a methoxy group at position 6, R2 is Br, and R3 is -CH3, providing a methoxy group at position 3:

[0061] The pharmaceutical compositions disclosed herein may be applied to health conditions characterized by neuronal excitability due to elevated glutamatergic neurotransmission, decreased gamma-amino-butyric acid (“GABA”) mediated inhibitoryneurotransmission, referred to as GABAergic neurotransmission, or both. The API to be used in the pharmaceutical compositions disclosed herein show an acute decrease in presynaptic glutamate release in neocortical layer ll / lll pyramidal neurons without statistically significant effects on GABAergic neurotransmission, providing potential therapeutics for modulating neuronal hyperexcitability through targeted correction of excitatory / inhibitory balance in cortical circuits.

[0062] Transcriptom ic data demonstrates that TCB-2 reverses transcriptom ic changes associated with bipolar disorder, restoring a gene expression profile consistent with being unaffected by of bipolar disorder. Electrophysiology data demonstrates that acute exposure to TCB-2 rapidly modulates action potential firing frequency in cortical pyramidal neurons. The acute effect on neuronal excitability is comparable to physiological changes observed only after several weeks of chronic lithium carbonate exposure, and with different side effect risk profiles than lithium carbonate.

[0063] Patch clamp, transcriptional and Genome-wide association studies (“GWAS”) data together are consistent with TCB-2 and other compounds herein being used in treatment of bipolar disorder, including bipolar 1 , bipolar 2 and cyclothymic disorder through acute or chronic application of the pharmaceutical compositions described herein. The pharmaceutical compositions described herein may be applied in treatment of bipolar disorder with potentially more rapid onset of beneficial effects and mitigation of side effects associated with lithium carbonate, a standard of care therapeutic for bipolar disorder.

[0064] The GWAS and electrophysiology data together also support application of the compositions disclosed herein for treatment of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder.

[0065] The compounds described herein may be prepared into a pharmaceutical drug product, or otherwise put to use, applied in a method, used in the preparation of a medicament or otherwise applied therapeutically. The pharmaceutical drug product maybe formulated to provide therapeutic benefit across different treatment paradigms, including chronic administration to maintain symptom relief and acute administration to address immediate symptom onset.

[0066] For chronic treatment, the pharmaceutical drug product may be administered over an extended period to sustain therapeutic effects, reduce symptom severity, and prevent relapse. Chronic administration may involve continuous or repeated dosing according to a regimen determined by a healthcare provider.

[0067] For acute treatment, the pharmaceutical drug product may be used to provide rapid relief from one or more symptoms of bipolar disorder or other health conditions. Acute administration may be intended for episodes of symptom exacerbation or breakthrough symptoms requiring immediate intervention.

[0068] Regardless of whether the pharmaceutical drug product is administered chronically or acutely, it may be formulated or dosed in a manner that allows for same- day relief of symptoms. Same-day relief may involve mechanisms such as rapid absorption, optimized pharmacokinetics, or targeted delivery strategies to achieve therapeutic concentrations in a short period following administration.

[0069] Rapid Onset

[0070] The pharmaceutical drug product may be formulated to provide relief from at least one symptom of the health condition within the same day as ingestion. The onset of therapeutic effects may vary depending on factors such as the pharmacokinetic properties of the compound, the route of administration, and patient-specific variables. In some embodiments, relief may occur within about 4 hours, 2 hours, 1 hour, 30 minutes, 15 minutes, 5 minutes, or even about 1 minute or less following ingestion.

[0071] The rapid onset of relief may be achieved through various formulation strategies, including the use of fast-dissolving oral dosage forms, sublingual or buccal delivery systems, parenteral administration, or inhalation-based delivery. For example, orally disintegrating tablets, effervescent formulations, or liquid preparations may enhance absorption and facilitate faster therapeutic effects. Similarly, parenteral formulations such as intravenous or intramuscular injections may provide direct systemic availability of the compound, reducing the time to clinical effect. Inhalation-based deliverymethods, such as dry powder inhalers or metered-dose inhalers, may enable rapid absorption through the pulmonary route, leading to faster symptom relief.

[0072] The timing and extent of symptom relief may be evaluated using objective clinical measures, patient-reported outcomes, or biomarker-based assessments. Factors such as the severity of the health condition, baseline symptom intensity, and concomitant treatments may influence the observed response time. The pharmaceutical drug product may be particularly beneficial for patients requiring immediate intervention for acute symptom flare-ups or breakthrough episodes, where delayed onset of action may compromise treatment efficacy or patient wellbeing.

[0073] The pharmaceutical drug product may provide relief from symptoms of the health condition that is associated with a clinically measurable improvement. Such improvement may be assessed using standardized clinical scales, biomarker changes, functional assessments, or patient-reported outcomes. The pharmaceutical drug product may be administered as part of a broader treatment regimen that includes a separate chronic treatment product.

[0074] Use Alongside Lithium or other Chronic Maintenance Drugs

[0075] In cases where the health condition is bipolar disorder, the pharmaceutical drug product may be used alongside a chronic lithium carbonate treatment regimen. The pharmaceutical drug product may allow for a reduction in the required lithium carbonate dose while maintaining therapeutic efficacy, potentially minimizing the risk of lithium- related adverse effects. In some embodiments, the pharmaceutical drug product may serve as a breakthrough treatment option for patients experiencing symptom exacerbation despite ongoing lithium carbonate therapy.

[0076] Co-administration of the pharmaceutical drug product including the compounds described herein with lithium carbonate may result in a reduced incidence or severity of lithium-associated side effects. Chronic lithium therapy is known to cause adverse effects such as cognitive impairment, sedation, tremors, and emotional blunting. The pharmaceutical drug product may mitigate these effects by either reducing the total lithium burden or counteracting specific neurochemical mechanisms contributing to these side effect.

[0077] The pharmaceutical drug product may be formulated in a manner that facilitates combination use with lithium carbonate, such as through compatible dosing schedules, formulation strategies that optimize lithium pharmacokinetics, or adjunctive administration routes that allow for independent dose titration. The ability to use the pharmaceutical drug product either as a chronic adjunct or as an as-needed breakthrough therapy may provide greater flexibility in managing bipolar disorder while improving overall patient adherence and quality of life.

[0078] Dosing

[0079] The pharmaceutical drug product may be formulated for oral, parenteral, inhalation, or transdermal administration of the compounds described herein. The specific formulation may be selected based on factors such as bioavailability, patient compliance, and the desired onset of therapeutic action. Oral formulations may include solid or liquid dosage forms, while parenteral formulations may include injectable solutions, suspensions, or depot formulations. Inhalation and transdermal formulations may be used for alternative routes of administration that bypass first-pass metabolism and enable rapid systemic absorption.

[0080] The pharmaceutical drug product may be formulated to contain a specific amount of the TCB-2 or other compounds within structure (I). In some embodiments, the dosage form may include between about 1 pg and about 50 pg of the compound. In other embodiments, the dosage form may include between about 50 pg and about 100 pg, between about 100 pg and about 250 pg, between about 250 pg and about 500 pg, between about 500 pg and about 800 pg, or between about 800 pg and about 1 ,500 pg of the compound.

[0081] Higher dose formulations may also be used, depending on therapeutic needs. In some embodiments, the pharmaceutical drug product may include between about 1 ,500 pg and about 5 mg of the TCB-2 or other compounds within structure (I). In other embodiments, the dosage form may contain between about 5 mg and about 10 mg, between about 10 mg and about 20 mg, between about 20 mg and about 50 mg, between about 50 mg and about 100 mg, or between about 100 mg and about 250 mg of TCB-2 or other compounds within structure (I). The appropriate dose may depend on factorssuch as the severity of the condition being treated, patient-specific pharmacokinetics, and the intended duration of therapeutic effect.

[0082] Formulations

[0083] The pharmaceutical drug product may be formulated in a variety of dosage forms to accommodate different routes of administration, optimize therapeutic effects, and improve patient compliance. The selection of a specific dosage form may depend on factors such as the desired onset of action, bioavailability, patient preferences, and clinical considerations.

[0084] For oral administration, the pharmaceutical drug product may be formulated as a tablet, capsule, softgel, granule, powder, suspension, solution, emulsion, lozenge, orally disintegrating tablet, effervescent tablet, sublingual material, buccal tablet, syrup, or elixir. Oral formulations may be designed for immediate release, extended release, or delayed release, depending on therapeutic needs. Fast-dissolving and sublingual formulations may be used to accelerate absorption and onset of action.

[0085] For parenteral administration, the pharmaceutical drug product may be provided as a solution for injection, suspension for injection, emulsion for injection, lyophilized powder for reconstitution, depot injection, infusion solution, pre-filled syringe, or auto-injector. The formulation may be suitable for administration via intravenous (IV) push, IV drip, intramuscular (IM) injection, subcutaneous (SC) injection, intradermal injection, intraperitoneal injection, or intrathecal injection. Parenteral formulations may be used to achieve rapid systemic absorption, bypass first-pass metabolism, or enable administration in patients unable to take oral medications.

[0086] For inhalation-based delivery, the pharmaceutical drug product may be formulated as a nebulizer solution, nebulizer suspension, dry powder inhaler (DPI), metered-dose inhaler (MDI), or soft mist inhaler (SMI). Inhalation-based delivery may be used for rapid absorption via the pulmonary route, offering a non-invasive alternative to parenteral administration with a fast onset of action.

[0087] For transdermal administration, the pharmaceutical drug product may be formulated as a patch, gel, cream, ointment, spray, film, microneedle array, emulsion, reservoir system, or matrix system. Transdermal delivery may provide sustained drugrelease over an extended period while avoiding gastrointestinal metabolism and fluctuations in plasma drug levels.

[0088] The pharmaceutical drug product may further comprise a pharmaceutically acceptable carrier, diluent, or excipient. Such components may be included to enhance drug stability, solubility, absorption, or patient tolerability. The choice of excipients may be guided by factors such as formulation compatibility, shelf-life considerations, and the desired pharmacokinetic profile of the active compound.

[0089] The pharmaceutical drug product may include labeling that provides clear guidance on intended use, ensuring appropriate administration and compliance with regulatory requirements. The label may specify that the pharmaceutical drug product is indicated for symptomatic relief or other treatment of the health condition. The label may also include relevant clinical information, dosing recommendations, contraindications, warnings, and other safety-related details to inform healthcare providers and patients.

[0090] The pharmaceutical drug product may be provided with instructions for use that outline the appropriate method of administration for achieving symptomatic relief or other therapeutic effects. The instructions may specify the ingestion of a dosage form containing a pharmaceutically effective amount of the compound. Depending on the formulation, the instructions may include details on whether the pharmaceutical drug product should be taken with or without food, any necessary preparation steps, such as reconstitution of a lyophilized powder, and any precautions regarding concomitant medications.

[0091] In some embodiments, the pharmaceutical drug product may include both an indicated use for symptomatic relief or other treatment of the health condition and detailed instructions for use on the label. The labeling may ensure that patients and healthcare providers have clear guidance on the appropriate dosing regimen, administration method, and expected therapeutic benefits. The inclusion of such information may facilitate regulatory approval and compliance with industry standards for pharmaceutical labeling.

[0092] The pharmaceutical drug product may also be provided in combination with a medical device that facilitates administration or ingestion of the dosage form. In such embodiments, the dosage form may be incorporated into a medical device such as anauto-injector, pre-filled syringe, inhaler, transdermal patch, or other drug delivery system. The integration of the pharmaceutical drug product with a medical device may enhance ease of administration, improve patient adherence, or enable controlled release of the active compound. The medical device may be designed for single-use or reusable applications and may include features such as dose counters, safety mechanisms, or connectivity for remote monitoring of drug usage.

[0093] Bipolar Disorder

[0094] Bipolar disorders include bipolar I, bipolar II, cyclothymia and other bipolar disorders. Bipolar I disorder is defined as at least one manic episode, with or without depressive episodes. Bipolar II disorder is defined as at least one hypomanic episode and one major depressive episode. A hypomanic episode carries the general indicia of a manic episode but with a lower intensity than a full manic episode. Cyclothymia is a milder expression of bipolar disorder that carries hypomanic episodes with periods of depression that do not meet the criteria for major depressive episodes. Other conditions that have overlapping symptoms with bipolar disorder include attention deficit hyperactivity disorder, personality disorders, schizophrenia and substance use disorder.

[0095] Bipolar disorder is a highly heritable mental illness. Family studies have demonstrated that bipolar disorder aggregates in families, finding the recurrence risk in first-degree relatives of affected bipolar disorder patients to be approximately 9% (Smoller and Finn, 2003), nearly 10 times that of the general population (Tsuang and Faraone, 1990; Kessler et al., 1997). Twin studies have found concordance rates for bipolar disorder to be significantly greater in monozygotic twin pairs (who are genetically identical) than among dizygotic twin pairs (who share, on average, 50% of their genes), establishing that the familiarity of bipolar disorder is predominantly due to genetic rather than shared environmental factors (Kendler et al., 1995; McGuffin et al., 2003; Kieseppa et al., 2004). Based on twin and family studies, the heritability of bipolar disorder is estimated at 60-85% (Bienvenu et al., 2011 ; Song et al., 2015), among the highest estimate for any psychiatric disorder.

[0096] Despite the high estimate of heritability for bipolar disorder, the genetic etiology of bipolar disorder remains poorly understood. Linkage studies have failed to identify rare genetic variants with large effect sizes, suggesting that the genetic etiologyof bipolar disorder likely involves many common low penetrant variants (McQueen et al., 2005a).

[0097] Management of bipolar disorder patients involves the acute treatment of manic or hypomanic episodes in addition to maintenance therapy to prevent relapses and further episodes. Pharmacological interventions are often applied to treatment of acute episodes. Nonpharmacological treatments such as electroconvulsive therapy (“ECT”) may also be used as a monotherapy or an adjunctive therapy.

[0098] FDA-approved medications for the treatment of acuta mania in adults include mood stabilizers (e.g. lithium carbonate, carbamazepine, etc.) and antipsychotics (e.g. aripiprazole etc.). Differences in the reported efficacy of FDA-approved therapies for the treatment of mania are small and their adverse-effect profiles vary widely (Cipriani et al., 2011 ; Yildiz et al., 2014; Fang et al., 2017).

[0099] Bipolar disorder depression treatment may include administration of FDA- approved antipsychotics (e.g. lurasidone), or off-label use of anticonvulsants and antidepressants (Sidor & MacQueen, 2011 ; Pacchiarotti et al., 2013; McGirr et al., 2016; Vieta and Garriga, 2016). Standard antidepressants have repeatedly failed to show benefit in randomized, placebo-controlled trials and existing mood stabilizers fail to provide benefit to ~2 / 3 of bipolar disorder patients (Nemeroff et al., 2001 ; Sachs et al., 2007). Some atypical antidepressants have demonstrated efficacy but only benefit a subset of bipolar disorder patients (Tohen et al., 2003; Thase et al., 2006). Nonpharmacological treatments for bipolar depression include ECT, repetitive transcranial magnetic stimulation, deep brain stimulation, vagus nerve stimulation, lifestyle interventions and psychotherapies.

[0100] Long-term management of bipolar disorder patients typically involves pharmacological treatment (most commonly a mood stabilizer alone or in combination with an antipsychotic or an antidepressant), psychological therapies, and lifestyle approaches (Geddes and Miklowitz, 2013; Vieta et al., 2013; Saunders et al., 2015). Lithium carbonate remains one of the most effective drugs approved for mitigating manic and depressive episodes. Long-term use of lithium carbonate is associated with adverse effects including sedation, cognitive changes, decline in renal function, hypothyroidism and hypercalcemia (Miura et al., 2014; Shine et al., 2015).

[0101] Bipolar disorders intersect with other health conditions, some commonly considered alongside bipolar disorder and others less so, characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission. Pathologically elevated presynaptic glutamate release refers to a level of elevated presynaptic glutamate release resulting in disease, disorder, harm or other sub optimal function of cells, organs, tissue or other characterizations of an individual, animal or other organism, whether or not clinically diagnosable as a specific disease, syndrome or other healthcare issue. Pathologically decreased GABAergic neurotransmission refers to a level of decreased GABAergic neurotransmission resulting in disease, disorder, harm or other sub optimal function of cells, organs, tissue or other characterizations of an individual, animal or other organism, whether or not clinically diagnosable as a specific disease, syndrome or other healthcare issue. The health conditions may include bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. In addition to bipolar disorder, bipolar 1 , bipolar 2, and cyclothymic disorder, the compounds described herein, including TCB-2, may be applied to treatment of other conditions characterized by one or more of neuronal excitability, increased presynaptic glutamate release, or decreased GABAergic neurotransmission.

[0102] Genetic Etiology of Bipolar Disorder

[0103] Genome-wide association studies (“GWAS”) have provided additional insights into the genetic etiology of bipolar disorder. A large GWAS was recently completed involving nearly 42,000 bipolar disorder patients, identified 64 genetic loci that are significantly associated with the disorder: LINC01748, NUF2, LMAN2L, SCN2A, CERS6, PCGEM1, rs2719164, TRANK1, ITIH1, MDFIC2, CD47, KIAA1109, ADCY2, H0MER1, SSBP2, KDM3B, D0CK2, MHC, POU3F2, SYNE1, RPS6KA2, MAD1L1, THSD7A, SP4, MPP6, SRPK2, PLXNA4, MRPS33, miR124-1, MSRA, RP1-84O15.2, PLEC, ZCCHC7, TUBBP5, CACNB2, ANK3, ADO, ADD3, FADS2, FKBP2, PACS1, PC,SHANK2, 0DZ4, CACNA1C, CUL4A, BCL11B, C15orf53, STARD9, H0MER2, ZNF592, FURIN, C16orf72, GRIN2A, RPL13, RTN4RL1, ERBB2 (rs11870683), ERBB2 (rs61554907), HDAC5, STK4, WFDC12, KCNB1, 0SBPL2, and SLC25A 17 (Mullins et al., 2021 ). The identified variants are common (minor allele frequency > 10%), have small effect sizes (ORs <1 .2), and explain only a small proportion of the genetic contribution to bipolar disorder (SNP-based heritability, ~18%), which is consistent with thousands of low-penetrance variants contributing to the etiology of bipolar disorder.

[0104] Data from RNA sequencing studies on post-mortem brain tissue samples recovered from patients diagnosed with bipolar disorder may be applied to investigation of biological mechanisms and pathology related to bipolar disorder (Elashoff et al., 2007; Akula et al., 2014; Cruceanu et al., 2015; Kim et al., 2016; Darby et al., 2016; Akula et al., 2016; Hu et al., 2016; Pacifico and Davis, 2017; Ramaker et al. 2017; Gandal et al., 2018; Luykx et al., 2019; Zandi et al., 2022). Numerous differentially expressed genes have been identified, including genes previously identified by GWAS of bipolar disorder patients such as CACNA1C, DTNA, F0XP1, GNG2, ITPR2, LSAMP, NPAS3, NC0A2, NTRK3, SCN2A, and GRIN2A (Nurnberger et al., 201 ; Zandi et. Al., 2022).

[0105] Many of the GWAS and RNA sequencing studies of bipolar disorder patients identify biological pathways and process implicated with genetic associations and changes in gene expression. Dysregulation of immune and inflammation-related signaling pathways has been observed (Kim et al., 2016; Pacifico and Davis, 2017; Gandal et al., 2018; Zandi et al., 2022). Corticotropin-releasing hormone signaling, cardiac [3-adrenergic signaling, phospholipase C signaling, glutamate receptor signaling, endothelin 1 signaling, and cardiac hypertrophy signaling have also been implicated in bipolar disorder (Nurnberger et al., 2014). The dysregulation of signaling pathways related to synaptic density, post-synaptic membranes, G protein-coupled receptor regulation, mRNA processing, ribosome biogenesis, antigen degradation, GABAergic signaling, neuroplasticity, circadian rhythms, GTPase binding, and oxidative phosphorylation have also been reported (Akula et al., 2014; Cruceanu et al., 2015; Akula et al., 2016; Darby et al., 2016; Pacifico and Davis, 2017; Zandi et al., 2022).

[0106] Phenalkylamine Drugs

[0107] Activity at the 5-HT2A receptor is associated with the effects of lysergic acid diethylamide (“LSD”), N,N-dimethyltryptamine (“DMT”), 4-hydroxy-N,N- dimethyltryptamine (psilocin, including prodrugs such as psilocybin) and other psychedelic drugs that are commonly produced and used outside of compliance with regulatory structures, and that are also used in research related to brain function and mental health conditions. Typically, schizophrenia, bipolar disorder and certain other mental health conditions are contraindications for use of psychedelics for therapeutic purposes. Schizophrenia and bipolar disorder are common exclusion criteria for clinical trials involving psychedelic drugs.

[0108] Phenethylamine drugs substituted at position 2, and at one of position 5 or position 6, with methoxy or other alkoxy groups, and also substituted at position 4 with alkoxy, alkyl, halide or other substituents, are often strongly psychoactive. Naturally- occurring 3,4,5 trimethoxyphenethylamine (mescaline) has structural similarity to a common 2,4,5 substituted phenethylamine drug called 4-bromo-2,5-dim ethoxy phenethylamine (“2C-B”). 2C-B, and its amphetamine analogue, 4-bromo-2,5-dimethoxy amphetamine (“DOB”), are each strongly psychoactive and potent psychedelic drugs. 2C-B was discovered by Alexander Shulgin in 1974 and has become a relatively popular psychedelic drug in illicit markets. 2C-B and analogues of 2C-B are scheduled to drug control legislation in most countries. 2C-B and DOB are also agonists for the 5-HT2A receptor. Structure (III) is the structure of 2C-B and structure (IV) is the R-enantiomer of DOB:

[0109] TCB-2, shown above in structure (II) and other examples of the compounds as shown in structure (I), each carry structural similarity to 2C-B and to DOB. 2C-B is a phenethylamine, DOB is an amphetamine, and TCB-2 is a benzocyclobutylmethylamine, in each case with similar ring substitution. Relative to 2C-B, TCB-2 includes a secondaryalkyl group side chain bonded with the phenyl ring at position two of TCB-2 (which would be position six of 2C-B or DOB) and with the ethyl side chain at the beta position, forming a constrained four-membered ring between the phenyl ring and what in 2C-B would be the ethylamine side chain. Relative to DOB, the same is true, along with the absence of DOB’s alpha methyl group, which is the distinguishing structural feature between phenethylamines and amphetamines.

[0110] TCB-2 is a functionally selective agonist at the 5-HT2A receptor, TCB-2 is chiral with the R isomer having about a 22-fold greater affinity for the 5-HT2A receptor compared with the S isomer, resulting in a eudismic ratio of 43:1 (McLean et al., 2006).

[0111] Despite structural similarity between TCB-2 and 2C-B or other phenethylamine drugs, there is no clear evidence that TCB-2 is a psychedelic drug in humans. Anecdotal online accounts of psychoactive properties were, if presumed to be true and accurate, necessarily based on dosing with material that was sourced outside of regulated channels. It cannot be verified with any certainty which chemical or chemicals were in fact being used in anecdotes published online (Di Giovanni et al., 2018).

[0112] TCB-2 preferentially stimulates the phospholipase C pathway over the phospholipase A2 pathway, which is at variance with several psychedelic drugs that also bind the 5-HT2A receptor. TCB-2 exhibits subtle differences compared to 4-iodo-2,5- dimethoxy amphetamine (“DOI”) or LSD in some molecular, cellular and behavioral mouse studies (McLean et al., 2006; Di Giovanni et al., 2018). While TCB-2 binds to 5- HT2A, some of its effects in mice persist in the presence of strong 5-HT2A antagonists or in mice lacking 5-HT2A receptors.

[0113] TCB-2 has a 65-fold greater potency in stimulating phosphoinositide turnover than in producing arachidonic acid release. Since hallucinogenic psychoactive effects of psychedelic drugs are often correlated with arachidonic acid production, such functionally selective 5-HT2A receptor agonists may have attenuated psychoactive properties compared with hallucinogens such as LSD, DMT, 2C-B, DOB, DMT or psilocin and its prodrugs. However, studies with LSD-trained rats and DOI-trained rats indicate that TCB-2 may have psychoactive properties in rats (McLean et al., 2006).

[0114] While unclear whether TCB-2 is psychoactive as compared with other similarly structured drugs, use of TCB-2 would in many cases be contraindicated forschizophrenia or bipolar disorder, as clinical trials for psychedelic drugs such as LSD, DMT, 2C-B, DOB, DMT or psilocin and its prodrugs often define bipolar disorder and schizophrenia as exclusionary criteria.

[0115] Transcriptional Activity of TCB-2

[0116] Human transcriptom ic data analyzed as described herein supports modulation by TCB-2 of a complex transcriptional signature identified in biological samples from individuals affected by bipolar disorder. Modulation of the transcriptional signature associated with bipolar disorder by TCB-2 moves the transcriptional signature closer to a transcriptional signature associated with individuals who are not suffering from bipolar disorder.

[0117] Human transcriptomic data was obtained from post-mortem brain tissue and blood samples across more than 35 different cohorts recovered from patients suffering from bipolar disorder, with approximately 1 ,200 control samples.

[0118] The human transcriptomic bipolar disorder data was assessed with a suite of algorithms to identify relevant and recurrent disease biology defined by complex transcriptional signatures in patient samples. A compendium of drug-induced transcriptional profiles corresponding to over 22,000 unique compounds comprising of more than 400,000 gene expression profiles were used in the in silico screen.

[0119] Post-mortem brain tissue and blood samples were assessed with a data analysis platform to identify a complex transcriptional signature in bipolar disorder patients, including previously unknown genes and pathways associated with inflammation, metal homeostasis and detoxification, and vascular injury.

[0120] The algorithm used drug-induced transcriptional profiles and human disease transcriptional profiles to generate a ranked list of compounds based on the strength of simulated reversal of the human disease signature associated with bipolar disorder by drug-induced transcriptional profiles. Application of this approach identified TCB-2 treatment as having potential to reverse transcriptomic features of bipolar disorder, which is consistent with use of TCB-2 in treatment of treating bipolar disorder.

[0121] Drug-induced transcriptional data for TCB-2 was obtained from Readhead et al. (2018). The drug-induced transcriptional signature for TCB-2 reverses many features of the post-mortem transcriptional disease signature identified from biologicalsamples of post-mortem bipolar disorder patients. TCB-2 modulates specific genes and signaling pathways involved with vascular function, neuroinflammation, stress response, and metal ion homeostasis that are dysregulated in post-mortem tissue and blood samples from patients affected by bipolar disorder.

[0122] Electrophysiology Characterization

[0123] Electrophysiological data from whole-cell patch clamp studies described herein provides evidence TCB-2 treatment corrects electrophysiological deficits associated with bipolar disorder in a murine mutant model of bipolar disorder. The electrophysiological data confirms TCB-2 has potential application in treatment of individuals suffering from, diagnosed with or otherwise affected by a health condition characterized by one or more of neuronal excitability, increased presynaptic glutamate release, or decreased GABAergic neurotransmission. The health condition may include bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder. The bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder.

[0124] Multiple genetic studies have linked the Ank3 gene to bipolar disorder. The protein encoded by Ank3 is ankyrin-G. Ankyrin-G plays a crucial role in forming the axon initial segment (“AIS”), nodes of Ranvier, and GABAergic synapses (Ferreira et al., 2008; Lee et al., 2011 ). Mice carrying a mutation in the bipolar disorder risk gene Ank3 (Ank3 p.W1989R) exhibit deficits in inhibitory synaptic density, exhibit a reduction in GABAergic neurotransmission and exhibit an increase in excitability of pyramidal neurons. The resulting excitatory / inhibitory imbalance is also observed in bipolar disorder patients (Zhu et al., 2017; Nelson et al., 2020). Identification of a bipolar disorder family carrying the same variant as the Ank3 p.W1989R mouse underscores the model's relevance in understanding ankyrin-dependent inhibitory signaling in bipolar disorder. Chronic lithium or valproate treatment, cornerstone pharmacotherapies in bipolar disorder management, successfully reverses both electrophysiological and behavioral deficits observed in theAnk3 p.W1989R mice (Caballero-Floran et al., 2023; Zhu S et al., 2017). This crucial finding underscores the value of the Ank3 mutant mice model as a relevant system for the evaluation of novel therapeutic agents in bipolar disorder.

[0125] Whole cell voltage-clamp recordings from layer ll / lll cortical pyramidal neurons from C57BI6 / J and Ank3 p.W1989R mice assessed single action potential properties, maximum firing frequency, GABAergic neurotransmission through inhibitory postsynaptic currents (“sIPSCs”), and glutamatergic neurotransmission through excitatory postsynaptic currents (“EPSCs”) in pyramidal neurons. These assessments were conducted under control conditions (saline vehicle) and following bath application of 1 pM TCB-2 for 8 minutes. The C57BI6 / J mice were provided as a negative control modelling an individual not experiencing bipolar disorder. The Ank3 mutant mice were provided as a positive control modelling an individual experiencing bipolar disorder.

[0126] After administration of TCB-2, of saline vehicle only, or without administration exposure, the mice were anesthetized with isoflurane and sacrificed by decapitation. All procedures are by approved UM IACUC protocol PR000010191.

[0127] Murine brain was quickly removed from the skull after sacrifice and placed in 4°C slicing solution containing 62.5 mM NaCI, 2.5 mM KCI, 1.25 mM KH2PO4, 26 mM NaHCOa, 5 mM MgCl2, 0.5 mM CaCl2, 20 mM glucose and 100 mM sucrose. Solution pH was maintained at 7.4 by NaHCCh buffer saturated with O2 / CO2, 95 / 5% respectively.

[0128] Coronal brain slices of 300 to 350 pm thickness, targeted from layers II and III of the somatosensory cortex, were cut with a microtome VF-300 CompresstomeTM (Precisionary instruments, Natick MA). The brain slices were transferred to a holding chamber and maintained at room temperature in artificial cerebrospinal fluid (“ACSF”) for at least 1 hour before recording. The ACSF included 125 mM NaCI, 2.5 mM KCI, 1.25 mM KH2PO4, 26 mM NaHCOs, 1 mM MgCl2, 2 mM CaCl2, and 20 mM glucose, pH 7.4 (with 95%O2 and 5%CO2 bubbling through the solution).

[0129] After equilibration, individual brain slices were transferred to a recording chamber of about 300 pL volume continuously perfused with ACSF. Recording micropipettes were pulled from borosilicate glass capillaries (P-97; Sutter Instruments, Novato, CA) for a final resistance of 5 to 7 MQ. The recording micropipettes were filled with an internal solution containing in 135 mM K-Gluconate, 4 mM NaCI, 0.4 mM GTP, 2mM Mg-ATP,0.5 mM CaCh, 5 mM EGTA and 10 mM 4-(2-hydroxyethyl)-1 - piperazineethanesulfonic acid (“HEPES”) buffer adjusted to pH 7.25.

[0130] Excitatory glutamatergic pyramidal neurons in layers II and III of the somatosensory cortex of the somatosensory cortex were identified using a Nikon Eclipse FN-1 microscope with a 40X water-immersion objective and a DAGE-MTI IR-1000 video camera. The recording micropipettes were sealed to the neurons and the membrane ruptured within the recording pipette, providing a whole-cell configuration.

[0131] Changes in potential were measured on a current-clamped system, Signals were recorded using an Axoclamp 700B amplifier (Axon Instruments, Union City, CA) with a 10 kHz low pass filter. Current clamp recordings were obtained from neurons in layers II and III of the somatosensory cortex.

[0132] Single action potential (“SAP”) properties were measured. The resting membrane potential is the neuron’s membrane potential when the neuron is not excited. The threshold is the minimum potential required to trigger an action potential. Rheobase refers to the lowest current that can induce an action potential. The SAP amplitude is the height of the action potential above the resting potential. The rate of membrane potential change during the action potential’s rise is described as dv / dt depolarization. Lastly, dv / dt repolarization is the rate of change as the membrane potential returns to the resting level after an action potential.

[0133] sIPSCs were measured using whole-cell voltage-clamp recordings. The neuron is maintained at a specific membrane potential. Currents were measured flowing through channels opened by GABA. Changes in frequency and amplitude of the currents can be monitored, after administration of TCB-2, after administration of saline vehicle or without administration of any substance to observe how this condition affects inhibitory transmission. Voltage-clamp experiments allow for precise control of membrane potential to isolate and measure the sIPSCs.

[0134] Whole-cell patch-clamp recordings with a high cell resistance of greater than 8 GQ before break-in were obtained for cells according to availability. The neurons were characterized electrophysiologically by applying negative and positive current pulses of 10 pA for 1000 ms to calculate the rheobase and the maximum firing frequencyresponse, and single positive pulses of 1 ms to measure the features of the SAP properties.

[0135] For gamma-aminobutyric acid (“GABA”) receptor-mediated currents, the 135 mM K-gluconate in the internal solution was replaced by 140 mM CsCI, and the recordings were acquired at 2 kHz with a holding potential of -70 mV.

[0136] Spontaneous inhibitory postsynaptic currents (“sIPSC”) were isolated pharmacologically with 10 pM 6-cyano-7- nitroquinoxaline-2, 3-dione (“CNQX”) and 100 pM DL-2-Amino-5-phosphonopentanoic acid, (“DL-AP-5”). CNQX is an a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid “AMPA” and kainite receptor antagonist. DL- AP-5 is an N-methyl-D-aspartate (“NMDA”) receptor antagonist. The frequency in Hz and amplitude in pA for synaptic events were analyzed using Minianalysis software (Synaptosoft Inc.).

[0137] CNQX is used to block AMPA and kainite glutamate receptors. Glutamate is the primary excitatory neurotransmitter in the central nervous system. By blocking these receptors, CNQX effectively reduces excitatory postsynaptic currents mediated by glutamate. Application of CNQX as a control helps isolate sIPSCs by removing background noise of excitatory signals.

[0138] DL-AP-5 is an NMDA antagonist, another type of glutamate receptor. NMDA receptors are known for their role in synaptic plasticity and memory functions but also contribute to excitatory postsynaptic currents. By blocking NMDA these receptors, DL- AP-5 further reduces excitatory background signals, facilitating isolation and characterization of sIPSCs.

[0139] In summary, sIPSCs were isolated pharmacologically using CNQX and DL- AP-5 by specifically blocking excitatory signals and mitigating potential interference with measurement of sIPSCs. Frequency and amplitude of sIPSCs recordings were performed using the glutamatergic blockers CNQX and DL-AP-5 before and after the acute application of CNQX and DL-AP-5, or application of vehicle only as a control.

[0140] Electrophysiology Results

[0141] Ank3 p.W1989R mice exhibit reduced GABAergic neurotransmission and an increase in pyramidal neuron excitability compared to wild-type mice (Caballero-Floran et al., 2023). In Ank3 p.W1989R mice, acute application of 1 pM TCB-2 resulted in astatistically significant reduction in the firing frequency of pyramidal neurons and corresponding decrease in sEPSC frequency. Importantly TCB-2 did not alter sEPSC amplitude, SAP properties, or sIPSC frequency or amplitude. While acute lithium administration at supraphysiological concentrations (3 to 20 mM) has been shown to impact synaptic transmission (Peineau et al., 2007; Colino et al., 1998), acute exposure at therapeutic plasma levels has no effect on electrophysiological deficits in Ank3 p.W1989R mice.

[0142] Fig. 1 shows a graph of the average action potential (“AP”) firing frequency, measured in hertz (Hz), as a function of injected current, quantified in picoamperes (pA), in layer ll / lll cortical pyramidal neurons from Ank3 p.W1989R mice. The x-axis represents the current injection in pA. The y-axis indicates the frequency of action potentials in Hz. Fig. 1 demonstrates a relationship between electrical stimulation and firing frequency of pyramidal neurons in the presence (white triangle data series) and absence (black triangle data series) of TCB-2 in the saline bath.

[0143] Fig. 2 shows a graph of the AP frequency, measured in hertz (Hz), as a function of injected current, quantified in picoamperes (pA), in layer ll / lll cortical pyramidal neurons from wild type C57BI6 / J mice. The x-axis represents the current injection in pA. The y-axis indicates the frequency of action potentials in Hz. Fig. 2 demonstrates a relationship between electrical stimulation and firing frequency of cortical pyramidal neurons in the presence (white circle data series) and absence (black circle data series) of TCB-2 in the saline bath. The data obtained in the absence of TCB-2 in the saline bath is a combination of data obtained in the absence of saline, and data obtained following application of saline without TCB-2. The two data sets that were combined for the black circle data series were not statistically significantly different from one another.Table 1 : Statistical Significance between AP Frequency Values

[0144] In Table 1 , statistical correlations were assessed between the action potential firing frequency values observed in different data sets to determine whether differences between data sets observed were significant.

[0145] As indicated in Table 1 , some difference was observed as between Ank3 p.W1989R mice in the absence of TCB-2 compared with wild type C57BI6 / J mice in the absence of TCB-2 (P value of 0.001 ).

[0146] As indicated in Table 1 , significant differences were observed in the firing frequency of layer ll / lll cortical pyramidal neurons following application of TCB-2 to either acute brain slices from either Ank3 p.W1989R mice or wild type C57BI6 / J mice (P value of <0.0001 ). The significant differences following application of TCB-2 to Ank3 p. W1989R mice were observed regardless of whether the reference point for application of TCB-2 to Ank3 p.W1989R mice was the Ank3 p.W1989R mice prior to exposure or the wild type C57BI6 / J mice prior to exposure. Similarly, the significant differences following application of TCB-2 to wild type C57BI6 / J mice were observed regardless of whether the reference point for application of TCB-2 to wild type C57BI6 / J mice was the wild type C57BI6 / J mice prior to exposure or the Ank3 p.W1989R mice prior to exposure.

[0147] As indicated in Table 1 , no significant differences were observed as between Ank3 p.W1989R mice treated with TCB-2 compared with wild type C57BI6 / J mice treated with TCB-2 (P value of 0.1879).

[0148] The decreased firing frequency of pyramidal neurons was shown to be due to presynaptic reduction of glutamatergic neurotransmission activity, in contrast with effects mediated by increased GABAergic neurotransmission, as is the case with several weeks of chronic lithium carbonate exposure.

[0149] Fig. 3A shows sEPSC frequency recorded from layer ll / lll pyramidal neurons from C57BI6 / J mice, with a control data set obtained before TCB-2 bath application (marked “Control”) and an active data set obtained after TCB-2 bath application (marked “TCB-2”). Fig. 3B shows sEPSC amplitude recorded from layer ll / lll pyramidal neurons from C57BI6 / J mice, with a control data set obtained before TCB-2 bath application (marked “Control”) and an active data set obtained after TCB-2 bath application (marked “TCB-2”). Application of TCB-2 resulted in a statistically significant reduction in sEPSC frequency, marked with an asterisk (*) between the Control and TCB-2 data sets in Fig. 3A, and without significant change to sEPSC amplitude, marked for no signal (ns) between the Control and TCB-2 data sets in Fig. 3B.

[0150] Fig. 4A shows sIPSC frequency recorded from layer ll / lll pyramidal neurons from C57BI6 / J mice, with a control data set obtained before TCB-2 bath application (marked “Control”) and an active data set obtained after TCB-2 bath application (marked “TCB-2”). Fig. 4B shows sIPSC frequency recorded from layer ll / lll pyramidal neurons from C57BI6 / J mice, with a control data set obtained before TCB-2 bath application (marked “Control”) and an active data set obtained after TCB-2 bath application (marked “TCB-2”). Application of TCB-2 resulted in no significant change to either frequency or amplitude of sIPSCs, with no signal (ns) being indicated between the Control and TCB-2 data sets in each of Figs. 4A and 4B.

[0151] sIPSCs occur naturally without deliberate stimulation across postsynaptic membranes of a neuron due to action of inhibitory neurotransmitters. Currents are mediated by neurotransmitters such as GABA or glycine. GABA or glycine bind to their respective receptors on the postsynaptic neuron, increasing permeability of the neuron's membrane to chloride ions, resulting in hyperpolarization and inhibition of the neuron. Administration of TCB-2 did not affect sIPSC frequency or amplitude, indicating preservation of baseline GABAergic neurotransmission. The mechanistic profile demonstrated by TCB-2 differentiates TCB-2 and other compounds of formula (I) from lithium carbonate, as acute lithium administration shows negligible effects on GABAergic neurotransmission, while chronic lithium administration, which requires weeks of exposure, significantly increases GABAergic neurotransmission.

[0152] SAP properties were also measured in C57BI6 / J mice before and after application of TCB-2. Application of TCB-2 did not result in statistically significant changes to resting membrane potential, threshold, rheobase, amplitude, dv / dt depolarization or dv / dt repolarization. The lack of impact on SAP properties is consistent with a mechanism of action based on presynaptic glutamatergic neurotransmission.

[0153] Figs. 1 and 2 demonstrate a decrease in action potential firing frequency of layer ll / lll cortical pyramidal neurons following application of TCB-2 to acute slices from C57BI6 / J mice or from Ank3 p.W1989R mice. Fig. 3A shows TCB-2 decreases sEPSC frequency, while Fig. 3B shows no significant change to sEPSC amplitude. Fig. 4A showsTCB-2 exposure results in no statistically significant change to sIPSC frequency, while Fig. 4B shows TCB-2 exposure results in no statistically significant change to sIPSC amplitude. SAP properties were unchanged following administration of TCB-2. Together, the electrophysiological data, particularly in view of the transcriptional data, are consistent with a presynaptic glutamatergic mechanism of action resulting in the decreased average action potential firing frequency of cortical pyramidal neurons observed in Figs. 1 and 2.

[0154] Chronic lithium treatment of over three weeks normalizes neuronal excitability in Ank3 p.W1989R mice, increasing GABAergic neurotransmission, possibly through GSK-3 inhibition (Caballero-Floran et al., 2023). Unlike lithium carbonate and valproic acid, which require prolonged treatment to manifest therapeutic effects in Ank3 p.W1989R mice, acute TCB-2 administration induces a rapid reduction in neuronal excitability following bath application to cortical brain slices. Effects of TCB-2 on Ank3 p.W1989R mice suggest acute reduction in pyramidal cell excitability without requiring chronic administration as with lithium carbonate.

[0155] Rapid onset of reduction in neuronal firing frequency as shown in Figs. 1 and 2, reduction in sEPSC frequency without significantly affecting sEPSC amplitude as shown in Fig. 3, and without significantly affecting sIPSC frequency or amplitude as shown in Fig. 4, together reveal a neuropharmacological mechanism for TCB-2 predominantly or entirely a result of reduction in presynaptic glutamatergic neurotransmission. Without being bound by any theory, and entirely consistently with the data in Figs. 1 to 4, and otherwise described in herein, a fast-acting presynaptic mechanism of action of TCB-2 in correcting transcriptom ic and electrophysiological deficits associated with bipolar disorder and other disorders may provide relief from symptoms of bipolar disorder through a distinct mechanism of action compared with lithium-dependent rescue of GABAergic inhibitory neurotransmission, as previously illustrated for lithium in Ank3 p.W1989R mice (Caballero-Floran et al., 2023). This distinction in the possible mechanism of action of TCB-2 in contrast with lithium's well- documented effects, requiring weeks of chronic treatment to achieve therapeutic effects, suggests TCB-2 as a favorable therapeutic option.

[0156] Use of acute or chronic TCB-2 may provide relief from symptoms of bipolar disorder or other health conditions, and relative to chronic use of lithium carbonate, mayprovide relief while mitigating common side effects associated with increased GABAergic neurotransmission resulting from use of lithium carbonate. Side effects of chronic lithium carbonate usage may include cognitive impairment, sedation, tremors, and emotional blunting. Each of these side effects may result from, or be exacerbated by, increased post-synaptic GABAergic neurotransmission resulting from use of lithium carbonate. Strong transcriptional, electrophysiological, and GWAS evidence align with the presynaptic mechanism action of TCB-2, further evidenced by the electrophysiology data shown in Figs. 1 and 2 and otherwise described here. With a mechanism of action independent of GABAergic neurotransmission, TCB-2 may present a therapeutic option for mitigating symptoms of bipolar disorder or ameliorating bipolar disorder, with lower risk, relative to chronic lithium use, of cognitive impairment, sedation, tremors, and emotional blunting.

[0157] Administration of TCB-2 to mice demonstrates evidence of a distinctive mechanism to attenuate neuronal hyperexcitability, presenting a compelling biological rationale for therapeutic application across a spectrum of central nervous system disorders. Major depressive disorder, autism spectrum disorder, schizophrenia and similar disorders are often linked to dysregulated neural activity. Any disorder correlated with dysregulated neural activity may potentially be treated by TCB-2 through TCB-2’s modulating effect on neuronal excitability. Similarly, in neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, where neuronal excitability contributes to symptomatology, TCB-2 could offer symptomatic relief. TCB-2’s potential extends to the acute management of migraines and the chronic conditions of multiple sclerosis and amyotrophic lateral sclerosis, where neuronal hyperexcitability plays a key role. TCB-2 might also be beneficial in addressing the heightened neural activity associated with anxiety disorders, neuropathic pain, chronic pain, traumatic brain injury, and stroke. Furthermore, TCB-2’s ability to stabilize neural firing could prove advantageous in conditions with a cyclical nature, such as premenstrual dysphoric disorder and seasonal affective disorder, where fluctuations in neural excitability are evident. GWAS and other data also indicates potential application to relief from symptoms of postpartum depression, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, fibromyalgia, and alcohol use disorder.

[0158] Definitions

[0159] Unless explicitly stated otherwise or evident from context, "about," when referring to a number, includes the stated value plus or minus 10%. When referring to a range, "about" extends from 10% below the lower limit to 10% above the upper limit.

[0160] Unless explicitly stated otherwise or evident from context, as used herein, "individual(s)," "subject(s)," and "patient(s)" refer to any mammal. In some embodiments, the mammal is human; in others, non-human. These terms do not require or imply supervision by a healthcare professional, whether constant or intermittent.

[0161] The terminology used herein describes specific embodiments and does not limit any embodiment. Unless explicitly stated otherwise or evident from context, the singular forms "a," "an," and "the" include the plural unless the context clearly indicates otherwise. The terms "comprises" and "comprising" indicate the presence of specified features, integers, steps, operations, elements, or components without excluding additional ones. Unless explicitly stated otherwise or evident from context, presenting a list of alternatives linked by "or" is to be interpreted inclusively and includes any combination of one or more of the listed items.

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[0184] Examples Only

[0185] In the preceding description, for purposes of explanation, numerous details are set forth in order to provide a thorough understanding of the embodiments. However, it will be apparent to one skilled in the art that these specific details are not required.

[0186] The above-described embodiments are intended to be examples only. Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art. The scope of the claims should not be limited by the particular embodiments set forth herein, but should be construed in a manner consistent with the specification as a whole.

[0187] As one non-limiting aspect of use of examples, throughout this disclosure, different embodiments are expressed using range formats. Such descriptions are provided for convenience and brevity, and should not be interpreted as rigid limitations on the scope of any embodiment. Any stated range should be understood to explicitly disclose all possible subranges, as well as individual numerical values within the range, to the tenth of the lower limit unless the context clearly indicates otherwise. For example, if a range from 5 to 15 is described, it should be understood to specifically disclose subranges such as 5 to 8, 5 to 10, 6 to 12, 7 to 15, 9 to 14, and so on, along with individual values within that range, such as 5.1 , 7, 9.5, 13, and 14.8. The principle applies regardless of the size of the range. The upper and lower boundaries of these subranges may independently be included within the smaller ranges and are considered disclosed, except where a specific limit is expressly excluded in the range description. If a range includes one or both of the boundary values, variations excluding either or both of those limits are also covered by the disclosure unless the context explicitly dictates otherwise.

Claims

CLAIMS1 . A pharmaceutical drug product comprising at least one dosage form, the dosage form comprising a pharmaceutically effective amount of a compound having structure(I):wherein R1 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3; R2 is selected from the group consisting of Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl, and thio-n-propyl; and R3 is selected from the group consisting of -CH3, - CH2CH3, -CH(CH3)2, and -CH2CH2CH3; or a pharmaceutically acceptable salt thereof; and the dosage form is formulated for the treatment of a health condition associated with one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission.

2. The pharmaceutical drug product of claim 1 wherein R1 is -CH3, R2 is Br and R3 is -CH3.

3. The pharmaceutical drug product of any one of claims 1 or 2 wherein the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder.

4. The pharmaceutical drug product of claim 3 wherein the health condition is a bipolar disorder.

5. The pharmaceutical drug product of claim 4 wherein the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder.

6. The pharmaceutical drug product of any one of claims 1 to 5 wherein the treatment comprises chronically maintaining relief of at least one symptom of the health condition.

7. The pharmaceutical drug product of any one of claims 1 to 5 wherein the treatment comprises acute relief from at least one symptom of the health condition.

8. The pharmaceutical drug product of any one of claims 1 to 5 wherein the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound.

9. The pharmaceutical drug product of claim 8 wherein the treatment results in relief within about 4 hours of ingestion of the compound.

10. The pharmaceutical drug product of claim 8 wherein the treatment results in relief within about 2 hours of ingestion of the compound.11 . The pharmaceutical drug product of claim 8 wherein the treatment results in relief within about 1 hour of ingestion of the compound.

12. The pharmaceutical drug product of claim 8 wherein the treatment results in relief within about 30 minutes of ingestion of the compound.

13. The pharmaceutical drug product of claim 8 wherein the treatment results in relief within about 15 minutes of ingestion of the compound.

14. The pharmaceutical drug product of claim 8 wherein the treatment results in relief within about 5 minutes of ingestion of the compound.

15. The pharmaceutical drug product of claim 8 wherein the treatment results in relief within about 1 minute of ingestion of the compound.

16. The pharmaceutical drug product of any one of claims 1 to 15 wherein the relief is associated with a clinically measurable improvement.

17. The pharmaceutical drug product of any one of claims 6 to 16 wherein the relief is provided in the context of treatment of the health condition with a separate chronic treatment product.

18. The pharmaceutical drug product of claim 17 wherein the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product.

19. The pharmaceutical drug product of any one of claims 1 to 18 wherein ingestion of the compound results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate.

20. The pharmaceutical drug product of any one of claim 19 wherein the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting.21 . The pharmaceutical drug product of any one of claims 1 to 20 wherein the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use.

22. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 1 pg and about 50 pg.

23. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 50 pg and about 100 pg.

24. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 100 pg and about 250 pg.

25. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 250 pg and about 500 pg.

26. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 500 pg and about 800 pg.

27. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg.

28. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg.

29. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 5 mg and about 10 mg.

30. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 10 mg and about 20 mg.31 . The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 20 mg and about 50 mg.

32. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 50 mg and about 100 mg.

33. The pharmaceutical drug product of claim 21 wherein the dosage form includes an amount of the compound of between about 100 mg and about 250 mg.

34. The pharmaceutical drug product of any one of claims 21 to 33 wherein the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir.

35. The pharmaceutical drug product of any one of claims 21 to 33 wherein the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, asubcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection.

36. The pharmaceutical drug product of any one of claims 21 to 33 wherein the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI).

37. The pharmaceutical drug product of any one of claims 21 to 33 wherein the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system.

38. The pharmaceutical drug product of any one of claims 21 to 37 wherein the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient.

39. The pharmaceutical drug product of any one of claims 1 to 38 wherein ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons.

40. The pharmaceutical drug product of any one of claims 1 to 38 wherein ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency.41 . The pharmaceutical drug product of any one of claims 1 to 38 wherein ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude.

42. The pharmaceutical drug product of any one of claims 1 to 38 wherein ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission.

43. The pharmaceutical drug product of any one of claims 1 to 38 wherein ingestion of the compound results in no statistically significant changes in single action potentials of pyramidal neurons.

44. The pharmaceutical drug product of any one of claims 1 to 38 wherein ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

45. The pharmaceutical drug product of any one of claims 1 to 44 further comprising a label including an indicated use for symptomatic relief or other treatment of the health condition.

46. The pharmaceutical drug product of any one of claims 1 to 45 further comprising instructions for use of the pharmaceutical drug product in symptomatic relief or other treatment of the health condition, the use including ingestion of the dosage form comprising the pharmaceutically effective amount of the compound.

47. The pharmaceutical drug product of any one of claims 1 to 44 further comprising a label, and the label including: an indicated use for symptomatic relief or other treatment of the health condition; instructions for use of the pharmaceutical drug product, including by ingestion of the dosage form comprising the pharmaceutically effective amount of the compound.

48. The pharmaceutical drug product of any one of claims 1 to 47, further comprising a medical device, and wherein the dosage form is incorporated into the medical device for facilitating administration or other ingestion of the dosage form.

49. A pharmaceutical drug product comprising at least one dosage form, the dosage form comprising a pharmaceutically effective amount of a compound having structure (H):a pharmaceutically acceptable salt thereof; and wherein the dosage form is formulated for the treatment of a health condition associated with one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission.

50. The pharmaceutical drug product according to claim 49, further comprising the additional features of any one of claims 3 to 48.51 . A method of treating an individual suffering from a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission, the method comprising: providing a pharmaceutically effective amount of a compound having structure (I); or a pharmaceutically acceptable salt thereof, for ingestion by the individual:wherein R1 is selected from the group consisting of -CH3, -CH2CH3, -CH(CHs)2, and -CH2CH2CH3; R2 is selected from the group consisting of Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl, and thio-n-propyl; and R3 is selected from the group consisting of -CH3, - CH2CH3, -CH(CH3)2, and -CH2CH2CH3.

52. The method of claim 51 wherein R1 is -CH3, R2 is Br and R3 is -CH3.

53. The method of any one of claims 51 or 52 wherein the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder.

54. The method of claim 53 wherein the health condition is a bipolar disorder.

55. The method of claim 54 wherein the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder.

56. The method of any one of claims 51 to 55 wherein providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for chronically maintaining relief of at least one symptom of the health condition.

57. The method of any one of claims 51 to 55 wherein providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for providing acute relief from at least one symptom of the health condition.

58. The method of any one of claims 51 to 55 wherein providing the pharmaceutically effective amount of the compound comprises providing an amount and on a schedule for providing relief from at least one symptom of the health condition within the same day as administration of the compound.

59. The method of claim 58 wherein the treatment results in relief within about 4 hours of ingestion of the compound.

60. The method of claim 58 wherein the treatment results in relief within about 2 hours of ingestion of the compound.61 . The method of claim 58 wherein the treatment results in relief within about 1 hour of ingestion of the compound.

62. The method of claim 58 wherein the treatment results in relief within about 30 minutes of ingestion of the compound.

63. The method of claim 58 wherein the treatment results in relief within about 15 minutes of ingestion of the compound.

64. The method of claim 58 wherein the treatment results in relief within about 5 minutes of ingestion of the compound.

65. The method of claim 58 wherein the treatment results in relief within about 1 minute of ingestion of the compound.

66. The method of any one of claims 51 to 65 wherein the relief is associated with a clinically measurable improvement.

67. The method of any one of claims 56 to 66 wherein the relief is provided in the context of treatment of the health condition with a separate chronic treatment product.

68. The method of claims 67 wherein the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product.

69. The method of any one of claims 51 to 68 wherein ingestion of the compound results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate.

70. The method of claim 69 wherein the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting.71 . The method of any one of claims 51 to 70 wherein the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use.

72. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 1 pg and about 50 pg.

73. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 50 pg and about 100 pg.

74. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 100 pg and about 250 pg.

75. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 250 pg and about 500 pg.

76. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 500 pg and about 800 pg.

77. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg.

78. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg.

79. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 5 mg and about 10 mg.

80. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 10 mg and about 20 mg.81 . The method of claim 71 wherein the dosage form includes an amount of the compound of between about 20 mg and about 50 mg.

82. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 50 mg and about 100 mg.

83. The method of claim 71 wherein the dosage form includes an amount of the compound of between about 100 mg and about 250 mg.

84. The method of any one of claims 71 to 83 wherein the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir.

85. The method of any one of claims 71 to 83 wherein the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an autoinjector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection.

86. The method of any one of claims 71 to 83 wherein the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI).

87. The method of any one of claims 71 to 83 wherein the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system.

88. The method of any one of claims 71 to 87 wherein the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient.

89. The method of any one of claims 51 to 88 wherein ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons.

90. The method of any one of claims 51 to 88 wherein ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency.91 . The method of any one of claims 51 to 88 wherein ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude.

92. The method of any one of claims 51 to 88 wherein ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission.

93. The method of any one of claims 51 to 88 wherein ingestion of the compound results in no statistically significant changes in single action potentials of pyramidal neurons.

94. The method of any one of claims 51 to 88 wherein ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

95. A method of treating an individual suffering from a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission, the method comprising: providing a pharmaceutically effective amount of a compound having structure (II) ; or a pharmaceutically acceptable salt thereof for ingestion by the individual:(II).

96. The method of to claim 95, further comprising the additional features of any one of claims 52 to 94.

97. A compound having structure (I):wherein R1 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3; R2 is selected from the group consisting of Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl, and thio-n-propyl; and R3 is selected from the group consisting of -CH3, - CH2CH3, -CH(CH3)2, and -CH2CH2CH3; or a pharmaceutically acceptable salt thereof; for use as a medicament.

98. The compound for use according to according to claim 97 wherein R1 is -CH3, R2 is Br and R3 is -CH3.

99. The compound for use according to any one of claims 97 or 98 wherein the medicament is for treatment of a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission.

100. The compound for use according to claim 99 wherein the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder.

101. The compound for use according to claim 100 wherein the health condition is a bipolar disorder.

102. The compound for use according to claim 101 wherein the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder.

103. The compound for use according to any one of claims 99 to 102 wherein the treatment comprises chronically maintenance of relief of at least one symptom of the health condition.

104. The compound for use according to any one of claims 99 to 102 wherein the treatment comprises acute relief from at least one symptom of the health condition.

105. The compound for use according to any one of claims 99 to 102 wherein the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound.

106. The compound for use according to claim 105 wherein the treatment results in relief within about 4 hours of ingestion of the compound.

107. The compound for use according to claim 105 wherein the treatment results in relief within about 2 hours of ingestion of the compound.

108. The compound for use according to claim 105 wherein the treatment results in relief within about 1 hour of ingestion of the compound.

109. The compound for use according to claim 105 wherein the treatment results in relief within about 30 minutes of ingestion of the compound.

110. The compound for use according to claim 105 wherein the treatment results in relief within about 15 minutes of ingestion of the compound.

111. The compound for use according to claim 105 wherein the treatment results in relief within about 5 minutes of ingestion of the compound.

112. The compound for use according to claim 105 wherein the treatment results in relief within about 1 minute of ingestion of the compound.

113. The compound for use according to any one of claims 99 to 112 wherein the relief is associated with a clinically measurable improvement.

114. The compound for use according to any one of claims 103 to 113 wherein the relief is provided in the context of treatment of the health condition with a separate chronic treatment product.

115. The compound for use according to claim 114 wherein the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product.

116. The compound for use according to any one of claims 97 to 115 wherein the use as a medicament results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate.

117. The compound for use according to claim 116 wherein the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting.

118. The compound for use according to any one of claims 97 to 117 wherein the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use.

119. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 1 pg and about 50 pg.

120. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 50 pg and about 100 pg.

121. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 100 pg and about 250 pg.

122. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 250 pg and about 500 pg.

123. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 500 pg and about 800 pg.

124. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg.

125. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg.

126. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 5 mg and about 10 mg.

127. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 10 mg and about 20 mg.

128. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 20 mg and about 50 mg.

129. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 50 mg and about 100 mg.

130. The compound for use according claim 118 wherein the dosage form includes an amount of the compound of between about 100 mg and about 250 mg.131 . The compound for use according to any one of claims 118 to 130 wherein the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, a lozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir.

132. The compound for use according to any one of claims 118 to 130 wherein the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an auto-injector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection.

133. The compound for use according to any one of claims 118 to 130 wherein the dosage form comprises a dosage form suitable for inhalation selected from the groupconsisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI).

134. The compound for use according to any one of claims 118 to 130 wherein the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system.

135. The compound for use according to any one of claims 118 to 134 wherein the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient.

136. The compound for use according to any one of claims 97 to 135 wherein the use as a medicament results in a reduction in action potential frequency at pyramidal neurons.

137. The compound for use according to any one of claims 97 to 135 wherein the use as a medicament results in a reduction in glutamatergic neurotransmission frequency.

138. The compound for use according to any one of claims 97 to 135 wherein the use as a medicament results in no statistically significant changes in glutamatergic neurotransmission amplitude.

139. The compound for use according to any one of claims 97 to 135 wherein the use as a medicament results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission.

140. The compound for use according to any one of claims 97 to 135 wherein the use as a medicament results in no statistically significant changes in single action potentials of pyramidal neurons.

141. The compound for use according to any one of claims 97 to 135 wherein the use as a medicament results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

142. A compound having structure (II):(II); or a pharmaceutically acceptable salt thereof; for use as a medicament.

143. The compound for use according to claim 142, further comprising the additional features of any one of claims 99 to 141.

144. Use of a compound having structure (I) in the treatment of an individual suffering from a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission:wherein R1 is selected from the group consisting of -CH3, -CH2CH3, -CH(CH3)2, and -CH2CH2CH3; R2 is selected from the group consisting of Br, I, Cl, methoxy, ethoxy, isopropyloxy, n-propyloxy, methyl, ethyl, isopropyl, n-propyl, thiomethyl, thioethyl, thioisopropyl, and thio-n-propyl; and R3 is selected from the group consisting of -CH3, - CH2CH3, -CH(CH3)2, and -CH2CH2CH3.

145. The use according to claim 144 wherein R1 is -CH3, R2 is Br and R3 is -CH3.

146. The use according to any one of claims 144 or 145 wherein the health condition is selected from the group consisting of bipolar disorder, major depressive disorder, postpartum depression, premenstrual dysphoric disorder, anxiety disorders, seasonal affected disorders, schizophrenia, autism spectrum disorders, Dravet Syndrome, Lennox-Gastaut syndrome, epilepsy, Alzheimer’s disease, Parkinson’s disease, multiple sclerosis, amyotrophic lateral sclerosis, migraine, chronic and neuropathic pain, fibromyalgia, traumatic brain injury, stroke, and alcohol use disorder.

147. The use according to claim 146 wherein the health condition is a bipolar disorder.

148. The use according to claim 147 wherein the bipolar disorder is selected from the group consisting of bipolar 1 , bipolar 2, and cyclothymic disorder.

149. The use according to any one of claims 144 to 148 wherein the treatment comprises chronic maintenance relief of at least one symptom of the health condition.

150. The use according to any one of claims 144 to 148 wherein the treatment comprises acute relief from at least one symptom of the health condition.

151. The use according to any one of claims 144 to 148 wherein the treatment results in relief from at least one symptom of the health condition within the same day as ingestion of the compound.

152. The use according to claim 151 wherein the treatment results in relief within about 4 hours of ingestion of the compound.

153. The use according to claim 152 wherein the treatment results in relief within about 2 hours of ingestion of the compound.

154. The use according to claim 152 wherein the treatment results in relief within about 1 hour of ingestion of the compound.

155. The use according to claim 152 wherein the treatment results in relief within about 30 minutes of ingestion of the compound.

156. The use according to claim 152 wherein the treatment results in relief within about 15 minutes of ingestion of the compound.

157. The use according to claim 152 wherein the treatment results in relief within about 5 minutes of ingestion of the compound.

158. The use according to claim 152 wherein the treatment results in relief within about 1 minute of ingestion of the compound.

159. The use according to any one of claims 144 to 158 wherein the relief is associated with a clinically measurable improvement.

160. The use according to any one of claims 149 to 159 wherein the relief is provided in the context of treatment of the health condition with a separate chronic treatment product.

161. The use according to claim 160 wherein the health condition is a bipolar disorder and the separate chronic treatment product is a lithium carbonate drug product.

162. The use according to any one of claims 144 to 161 wherein the use results in a reduced incidence or severity of at least one side effect associated with chronic use of lithium carbonate, relative to the incidence or severity of the at least one side effect as expected to result from chronic use of lithium carbonate.

163. The use according to claim 162 wherein the side effect is selected from the group consisting of cognitive impairment, sedation, tremors, and emotional blunting.

164. The use according to any one of claims 144 to 163 wherein the compound is formulated into a dosage form for oral use, parenteral use, inhalation or transdermal use.

165. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 1 pg and about 50 pg.

166. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 50 pg and about 100 pg.

167. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 100 pg and about 250 pg.

168. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 250 pg and about 500 pg.

169. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 500 pg and about 800 pg.

170. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 800 pg and about 1 ,500 pg.

171. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 1 ,500 pg and about 5 mg.

172. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 5 mg and about 10 mg.

173. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 10 mg and about 20 mg.

174. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 20 mg and about 50 mg.

175. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 50 mg and about 100 mg.

176. The use according to claim 164 wherein the dosage form includes an amount of the compound of between about 100 mg and about 250 mg.

177. The use according to any one of claims 164 to 176 wherein the dosage form comprises an oral dosage form selected from the group consisting of a tablet, a capsule, a softgel, a granule, a powder, a suspension, a solution, an emulsion, alozenge, an orally disintegrating tablet, an effervescent tablet, a sublingual material, a buccal tablet, a syrup, and an elixir.

178. The use according to any one of claims 164 to 176 wherein the dosage form comprises a parenteral formulation selected from the group consisting of a solution for injection, a suspension for injection, an emulsion for injection, a lyophilized powder for reconstitution, a depot injection, an infusion solution, a pre-filled syringe, an autoinjector, an intravenous (IV) push, an IV drip, an intramuscular (IM) injection, a subcutaneous (SC) injection, an intradermal injection, an intraperitoneal injection, and an intrathecal injection.

179. The use according to any one of claims 164 to 176 wherein the dosage form comprises a dosage form suitable for inhalation selected from the group consisting of a nebulizer solution, a nebulizer suspension, a dry powder inhaler (DPI), a metered-dose inhaler (MDI), and a soft mist inhaler (SMI).

180. The use according to any one of claims 164 to 176 wherein the dosage form comprises a transdermal dosage form selected from the group consisting of a patch, a gel, a cream, a ointment, a spray, a film, a microneedle array, an emulsion, a reservoir system, and a matrix system.

181. The use according to any one of claims 164 to 180 wherein the dosage form further comprises a pharmaceutically acceptable carrier, diluent or excipient.

182. The use according to any one of claims 144 to 181 wherein ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons.

183. The use according to any one of claims 144 to 181 wherein ingestion of the compound results in a reduction in glutamatergic neurotransmission frequency.

184. The use according to any one of claims 144 to 181 wherein ingestion of the compound results in no statistically significant changes in glutamatergic neurotransmission amplitude.

185. The use according to any one of claims 144 to 181 wherein ingestion of the compound results in no statistically significant changes in frequency or amplitude of GABAergic neurotransmission.

186. The use according to any one of claims 144 to 181 wherein ingestion of the compound results in no statistically significant changes in single action potentials of pyramidal neurons.

187. The use according to any one of claims 144 to 181 wherein ingestion of the compound results in a reduction in action potential frequency at pyramidal neurons in the absence of statistically significant changes in GABAergic neurotransmission.

188. Use of a compound having structure (II) or a pharmaceutically acceptable sale thereof in the treatment of an individual suffering from a health condition characterized by one or more of neuronal hyperexcitability, pathologically elevated presynaptic glutamate release, or pathologically decreased GABAergic neurotransmission:(H).

189. The use according to claim 188, further comprising the additional features of any one of claims 146 to 187.

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