Use of ibogaine in the treatment of central nervous system stroke

Abstract

There is described a method for treating the post-acute effects of CNS stroke in a patient in need thereof. The method comprises administering to the patient a therapeutically effective amount of ibogaine, botanical iboga extract, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

Description

USE OF IBOGAINE IN THE TREATMENT OF CENTRAL NERVOUS SYSTEM STROKECROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit under 35 U.S.C. §119(e) of provisional patent application S.N. 63 / 572,643, filed April 1, 2024, the contents of which are hereby incorporated by reference.BACKGROUND OF THE INVENTIONFIELD OF THE INVENTION

[0002] In one of its aspects the present invention relates to the treatment of neurological damage as well as symptoms related to central nervous system (CNS) stroke in a subject. In another of its aspects, the present invention relates to treatments to prevent the recurrence of CNS stroke in a subject. In yet another of its aspects, the present invention relates to a pharmaceutical composition useful for treatment of neurological damage as well as symptoms related to CNS stroke in a subject, and to prevent the recurrence of CNS stroke in a subject.DESCRIPTION OF THE PRIOR ART

[0003] CNS stroke is a group of encephalic disorders generated by pathological processes at the vascular level of the central nervous system. It is characterized by the modification of blood flow in one of the cephalic regions and is classified into two subtypes: ischemic and hemorrhagic. Ischemia is generated by the formation of a clot which obstructs blood flow in one of the cerebral vessels, occlusion of blood vessels can be transient or permanent manifestation. Hemorrhage involves the rupture of one of the vessels responsible for encephalic irrigation, causing an accumulation of blood product in the cerebral parenchyma or in the subarachnoid space (Lizano Salas, M., Me Donald Molina, C., & Tully Sancho, S. (2020). Fisiopatologia de la cascada isquemica y su influencia en la isquemia cerebral. Revista Medica Sinergia, 5(8), e555.; Arauz, Antonio, & Ruiz-Franco, Angelica. (2012). Enfermedad vascular cerebral. Revista de la Facultad de Medicina (Mexico), 55(3), 11-21.).

[0004] Every year, CNS strokes affect approximately 795,000 people in the United States, and 15 million people worldwide (World Health Organization Regional Office for the Eastern Mediterranean, (n.d.). Stroke, Cerebrovascular accident.). One in every four people over the age of 25 are estimated to have a CNS stroke in their lifetime (World Stroke Organization. (2022). Global Stroke Fact Sheet 2022.), and it is estimated to be the second highest leading cause of death, with an annual mortality rate of at least 5.5 million globally (Donkor E. S. (2018). Stroke in the 21st Century: A Snapshot of the Burden, Epidemiology, and Quality of Life. Stroke research and treatment, 2018, 3238165.). In addition to high mortality, CNS stroke also has high morbidity, and more than half of cases result in long-term chronic disability.

[0005] Disability following CNS stroke can include impaired motor control, fatigue, incontinence, pain, vision problems, and hemiplegia, which is weakness or paralysis of limbs on one side of the body. Therefore, the societal impacts of both direct medical and indirect economic costs of CNS stroke are enormous.

[0006] Standard interventions following CNS stroke events include surgical vascular procedures, thrombolytic medications that break down plaque resulting from vascular occlusion, and blood pressure management, followed by ongoing physiotherapy. These therapies have been effective in reducing mortality and morbidity, but not in reversing cellular damage or disability once it occurs. In other instances, treatments like hyperbaric oxygen therapy, stem cell therapy, and transcranial magnetic stimulation have been shown to reduce inflammation, promote neurogenesis, and restore blood flow to the affected brain areas, resulting in modest improvements to disability.

[0007] However, the vast majority of currently used drugs / therapies for CNS stroke are variously limited by incomplete efficacy, and comprehensive treatment strategies are still lacking.

[0008] Thus, there is a pressing need for therapeutic approaches / agents that are safe, efficacious, and well-tolerated. Ideally, such a therapeutic approach / agent would also concurrently reduce lesions in the patient that are associated with CNS stroke.SUMMARY OF THE INVENTION

[0009] It is an object of the present invention to obviate or mitigate at least one of the above- mentioned disadvantages of the prior art.

[0010] It is another object of the present invention to provide a novel method for treating CNS stroke.

[0011] Accordingly, in one of its aspects, the present invention provides a method for treating CNS stroke and reducing associated lesions in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

[0012] Thus, it has been surprisingly discovered that ibogaine can be used to concurrently treat CNS stroke and reduce its associated lesions in a patient.DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] Various terms used throughout this specification are intended to have the following meanings.

[0014] By "ameliorate" is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.

[0015] By "analog" is meant a molecule that is not identical, but has analogous functional or structural features. For example, an ibogaine analog retains the biological activity of ibogaine, while having certain modifications that enhance the analog's function relative to the reference compound. Such modifications could increase the analog's oral availability, or half-life.

[0016] In this specification, "comprises," "comprising," "containing" and "having" and the like can have the meaning ascribed to them in U.S. Patent law and can mean " includes," "including," and the like; "consisting essentially of or "consists essentially" likewise has the meaning ascribed in U.S. Patent law and the term is open-ended, allowing for the presence of more than that whichis recited so long as basic or novel characteristics of that which is recited is not changed by the presence of more than that which is recited, but excludes prior art embodiments.

[0017] By "effective amount" is meant the amount of a required to ameliorate the symptoms of a disease relative to an untreated patient. The effective amount of active compound(s) used to practice the present invention for therapeutic treatment of a disease varies depending upon the manner of administration, the age, body weight, and general health of the subject. Ultimately, the attending physician or veterinarian will decide the appropriate amount and dosage regimen. Such amount is referred to as an "effective" amount.

[0018] By "disease" is meant any condition or disorder that damages or interferes with the normal function of a cell, tissue, or organ. Examples of diseases include multiple sclerosis.

[0019] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0020] As used herein, the terms "treat," treating," "treatment," and the like refer to reducing or ameliorating a disorder and / or symptoms associated therewith. It will be appreciated that, although not precluded, treating a disorder or condition does not require that the disorder, condition or symptoms associated therewith be completely eliminated.

[0021] Unless specifically stated or obvious from context, as used herein, the term "or" is understood to be inclusive. Unless specifically stated or obvious from context, as used herein, the terms "a", "an", and "the" are understood to be singular or plural.

[0022] Unless specifically stated or obvious from context, as used herein, the term "about" is understood as within a range of normal tolerance in the art, for example within 2 standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein are modified by the term about.Methods of Use

[0023] The present invention provides methods of treating CNS stroke and related diseases and / or disorders or symptoms thereof which comprise administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formulae (e.g., ibogaine and ibogaine analogs, and all of their anomers) herein to a subject (e.g., a mammal such as a human). Thus, one embodiment is a method of treating a subject suffering from or susceptible to CNS stroke or symptoms thereof. The method includes the step of administering to the mammal a therapeutic amount of an amount of ibogaine or an ibogaine analog sufficient to treat the disease or disorder or symptom thereof, under conditions such that the disease or disorder is treated.

[0024] The methods herein include administering to the subject (including a subject identified as in need of such treatment) an effective amount of a compound described herein, or a composition described herein to produce such effect.

[0025] Identifying a subject in need of such treatment can be in the judgment of a subject or a health care professional and can be subjective (e.g., opinion) or objective (e.g., measurable by a test or diagnostic method).

[0026] The therapeutic methods of the invention (which include prophylactic treatment) in general comprise administration of a therapeutically effective amount of the compounds herein, such as a compound of the formulae herein to a subject (e.g., animal, human) in need thereof, including a mammal, particularly a human. Such treatment will be suitably administered to subjects, particularly humans, suffering from, having, susceptible to, or at risk for a disease, disorder, or symptom thereof.

[0027] Determination of those subjects "at risk" can be made by any objective or subjective determination by a diagnostic test or opinion of a subject or health care provider (e.g., genetic test, enzyme or protein marker, Marker (as defined herein), family history, and the like).

[0028] In one embodiment, the invention provides a method of monitoring treatment progress. The method includes the step of determining a level of diagnostic marker (Marker) (e.g., anytarget delineated herein modulated by a compound herein, a protein or indicator thereof, etc.) or diagnostic measurement (e.g., screen, assay) in a subject suffering from or susceptible to a disorder or symptoms thereof associated with CNS stroke, in which the subject has been administered a therapeutic amount of a compound herein sufficient to treat the disease or symptoms thereof. The level of Marker determined in the method can be compared to known levels of Marker in either healthy normal controls or in other afflicted patients to establish the subject's disease status.

[0029] In preferred embodiments, a second level of Marker in the subject is determined at a time point later than the determination of the first level, and the two levels are compared to monitor the course of disease or the efficacy of the therapy. In certain preferred embodiments, a pretreatment level of Marker in the subject is determined prior to beginning treatment according to this invention; this pre-treatment level of Marker can then be compared to the level of Marker in the subject after the treatment commences, to determine the efficacy of the treatment.

[0030] The invention further relates to methods for treatment and / or prevention of CNS stroke, including symptoms associated with CNS stroke, and / or other disease / disorder affecting the nervous system (e.g. central, peripheral) or muscle including symptoms thereof, in a subject in need thereof using the compounds and compositions described herein.

[0031] Subject within the scope of the present invention is a mammal, such as a human or a veterinary animal, exhibiting symptoms and / or suffering from, or diagnosed with, diseases / disorders described herein. The term "veterinary animal" refers to any animal cared for, or attended to by, a veterinarian, and includes companion (pet) animals and livestock animals, for example, a cat, a dog, and a horse (e.g., a race horse). Other mammals, e.g., such as those used as experimental models for CNS stroke, mice, rats, rabbits, nonhuman primates, such as monkeys, are also within the scope of the invention (e.g. induced embolism, arterial occlusion, etc.).

[0032] Herein, "CNS stroke" is used as per the expert consensus definition (An Updated Definition of Stroke for the 21st Century: A Statement for Healthcare Professionals from the American Heart Association / American Stroke Association. Sacco, R., 2013). Diagnostic criteriaused to identify a subject with CNS stroke would be apparent to a person of skill in the art. For example, a skilled individual would appreciate that clinically defined CNS stroke is based on "brain, spinal cord, or retinal cell death attributable to ischemia, based on neuropathological, neuroimaging, and / or clinical evidence of permanent injury." More recent diagnostic criteria for CNS stroke include the presence of characteristic areas on a computerized tomography (CT) scan or magnetic resonance imaging (MRI) scan.

[0033] CNS stroke is a clinical syndrome that commonly develops in people from 50 to 65 years of age and is characterized by the rapid development of focal neurological signs that persist for more than 24 hours, with no apparent cause other than vascular origin. It is classified into 2 sub types: ischemic and hemorrhagic strokes. Ischemic stroke is initiated by a series of biochemical reactions that occur due to obstruction of blood flow to the brain (Arauz, A., & Ruiz-Franco, A. (2012). Enfermedad vascular cerebral. Revista de la Facultad de Medicina (Mexico), 55(3), 11- 21.). Hemorrhagic stroke or hemorrhagic ictus occurs when a blood vessel ruptures, causing bleeding in or around the brain. This hemorrhage leads to swelling and increased pressure, resulting in damage to brain cells and tissues. Common causes of hemorrhagic stroke include high blood pressure, aneurysms, arteriovenous malformations, head injuries or clotting disorders (National Cancer Institute, (n.d.). Accidente cerebrovascular hemorragico). These subjects are within the scope of the present invention.

[0034] Intracerebral Hemorrhage (ICH) represents the second most common cause of stroke. It usually occurs due to rupture of small arteries, frequently due to vasculopathy associated with arterial hypertension, cerebral amyloid angiopathy (CAA), coagulopathies, among other vascular diseases. Hypertension-related vasculopathy is more related to ICH in non-lobar areas (such as basal ganglia, thalamus, cerebellum and brainstem), whereas CAA is usually more linked to lobar ICH. Several risk factors, such as advanced age, hypertension, CAA, smoking, excessive alcohol consumption, use of sympathomimetic drugs, anticoagulants and antiplatelet agents, contribute to the development of ICH (Tadi, P., Lui, F. (2024). Acute Stroke. StatPearls. Treasure Island, FL: StatPearls Publishing.).

[0035] About 5% of all strokes are caused by spontaneous subarachnoid hemorrhage (SAH), with approximately 85% of these cases due to rupture of an aneurysm. Other causes ofspontaneous SAH include the use of drugs such as amphetamines and cocaine, coagulopathies, rupture of arteriovenous malformations, and vascular rupture due to dural venous sinus thrombosis. Risk factors such as smoking, arterial hypertension, excessive alcohol consumption, advanced age, personal history of aneurysms or other SAH, and family history of intracranial aneurysms are associated with SAH.

[0036] Cellular damage following a stroke is caused by impairments in the cell membrane that lead to inadequate depolarization in the affected cells. Depolarization causes the release of excitatory amino acids, such as glutamic acid or glutamate, from presynaptic terminals. These amino acids are responsible for opening calcium channels in the postsynaptic neuron, through glutaminergic receptors such as AMPA and NMDA, and subsequently activate metabotropic receptors, thus facilitating the release of calcium from intracellular stores and increasing its concentration. A key regulator of the cellular calcium level is the sodium-calcium exchanger in the plasma membrane, which removes calcium using the incoming sodium pulse. Higher levels of calcium in cellular mitochondria leads a decrease in the production of adenosine triphosphate (ATP), which is essential for cell function, and increases the production of oxygen free radicals and cytochrome C release (Lizano Salas, M., Me Donald Molina, C., & Tully Sancho, S. (2020). Fisiopatologia de la cascada isquemica y su influencia en la isquemia cerebral. Revista Medica Sinergia, 5(8), e555.).

[0037] Clinical symptoms resulting from the cellular damage following CNS stroke include hemiplegia, insensitivity, loss of tactile and vibratory sensations, balance disorders, drooping of the eyelid (ptosis), diminished reflexes, visual field problems, motor coordination difficulties (apraxia) and language disorders (aphasia). These symptoms are due to damage to the neurons and brain pathways involved. Other diseases / disorders affecting nerves and muscles include, but are not limited to, weakness, muscle stiffness, pain, which can be burning, throbbing, aching, imbalance, asthenia or fatigue, depression, visual disturbances or loss, headache, loss of bowel or bladder control, ataxia of gait or limb movements, difficulty walking, difficulty with coordinated movements of the upper extremities, cognitive dysfunction, loss or aberrant sensation, muscle cramps or spasms, among others. Subjects exhibiting these symptoms are within the scope of the present invention.

[0038] Although the treatment of acute stroke injury has improved significantly, reducing mortality and morbidity, it remains one of the leading contributors to global disability. Even within high income countries, more than 50% of patients who undergo surgical interventions still experience disabling neurological deficits (Grefkes, C., Fink, G.R. Recovery from stroke: current concepts and future perspectives. Neurol. Res. Pract. 2, 17 (2020).). Post-stroke recovery depends on the brain's ability to structurally and functionally reorganize neurovascular networks. The combination of complementary therapies and medications can enhance repair processes and restore affected brain functions (Yao, Y.-Y., et al. (2021). Functional Disability After Ischemic Stroke: A Community-Based Cross-Sectional Study in Shanghai, China. Frontiers in Neurology, 12.). It is generally agreed that patients with minor deficits, who receive treatment and rehabilitation as early as possible, are more likely to experience a recovery of disability symptoms, while patients with more severe CNS damage as well as those in the chronic phase of recovery (later than 6 months) generally experience little to no improvement or worsening of their symptoms.

[0039] The hyperacute phase of treatment for CNS stroke (within the first 24 hours) focuses on minimizing mortality and the effect of brain injury. After this period, the focus is on treating any symptoms of disability. Currently, certain drugs and rehabilitation methods are available that promote brain repair by increasing vascular connectivity, functionally reorganizing neurovascular networks. These treatments have very limited efficacy in their ability to restore cellular function in the affected areas. An additional goal of ongoing treatment is to reduce the possibility of recurring CNS stroke events by closely managing blood pressure.Ibogaine

[0040] Ibogaine has been used as a botanical preparation from the root bark of Tabernanthe iboga for over 100 years both as a crude preparation; as a purified botanical drug that contains ibogaine and other alkaloids found in iboga root bark; as isolated ibogaine, which was marketed in France until about 1970; or more recently as semi -synthetic ibogaine that can be produced from voacangine or other similar alkaloids. The therapeutic use of ibogaine in all of these preparations is limited due to potentially adverse side effects. For example, in larger dosages ibogaine exhibits stimulant and hallucinogenic properties, and in addition, can induce temporaryataxia and tremors. At conventional doses, ibogaine causes these side effects in a majority of patients receiving treatment.

[0041] In the United States, ibogaine is classified as a Schedule I controlled substance. The use of ibogaine in humans is complicated by the fact that the ranges in the prior art are exceptionally broad (0.01 to 1000 mg / kg body weight). Furthermore, the ranges generally used to treat addiction (e.g., 15 mg / kg to 20 mg / kg) cause hallucinations and may be fatal. Dickinson, J., McAlpin, J., Wilkins, C., Fitzsimmons, C., Guion, P., Paterson, T., Greene, D., & Chaves, B. R. (2016). Clinical Guidelines for Ibogaine-Assisted Detoxification (1st ed., Version 1.1). The Global Ibogaine Therapy Alliance., accessed at http: / / ibogaineguidelines.com, which is incorporated herein by reference in its entirety for all of its methods, compositions and teachings.

[0042] "Ibogaine" refers to the compound:It should be understood that where "ibogaine" is mentioned herein, one more polymorphs of ibogaine can be utilized and are contemplated. Ibogaine is isolated from Tabernanthe iboga, a shrub of West Africa. Ibogaine can also be synthesized using known methods. See, e.g., Buchi, et al. (1966), J. Am. Chem Society, 88(13), 3099-3109 Unless specified otherwise, "ibogaine" as used herein refers to ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof. It may also refer to an ibogaine mixture, such as a botanical extraction of Tabernanthe iboga, or other alkaloids found present in it, including ibogamine, ibogaline, tabemanthine, coronoradine, voacangine, etc.Mechanism of Action

[0043] Ibogaine has complex pharmacology, which produce several therapeutic effects that are relevant to the treatment of stroke. Each of these effects, separately and together, are within the scope of the present invention.

[0044] During CNS stroke, the depolarization of cellular membranes induces the release from presynaptic terminals of excitatory amino acids such as glutamic acid or glutamate (Glu), in charge of opening calcium channels dependent on glutamatergic receptors such as acidoamino-3- hydroxy-5-methyl-4-Isoxazole (AMP A) and N-methyl-D-Aspartate (NMD A) in the postsynaptic neuron and subsequently, activate metabotropic receptors (diacylglycerol, inositol triphosphate, phosphocreatine) that help the release of calcium from intracellular deposits, producing an increase in calcium concentration (6). The unregulated and damaging release of glutamate, by activating NMDA receptors, causes an increase in sodium conductance, further aggravating brain damage causing cytotoxic edema resulting from the osmotic effect of this ion (4). Sustained neuronal depolarization has been proposed as part of the genesis of damage and death in cellular exci totoxi city through two processes by glutamate release with the recruitment of adjacent neurons and the inability to achieve adequate repolarization, which triggers cytotoxic edema and in some cases leads to neuronal death (Lizano Salas , M., Me Donald Molina , C., & Tully Sancho , S. (2020). Fisiopatologia de la cascada isquemica y su influencia en la isquemia cerebral. Revista Medica Sinergia, 5(8), e555. https: / / doi.org / 10.31434 / rms.v5i8.555).

[0045] Ibogaine increases glutamate production and almost completely inhibits glutamate uptake by cultured cortical astrocytes in mice (96%) and rats (97%) (Skolnick, P. (2001). Capitulo 3 La ibogaina como antagonista del glutamato: relevancia para sus supuestas propiedades antiadictivas. Los alcaloides: quimica y biologia, 55-62.). Extracellular glutamate concentrations are usually maintained at low levels by its Na-dependent transport into neurons and especially into astrocytes. Ibogaine inhibited both glutamate uptake by mouse cortical synaptosomes (neuronal transporters) and by mouse cortical astrocyte cultures. These results reinforce the proposal that high concentrations of ibogaine could increase extracellular glutamate, causing excitotoxic concentrations in the synaptic cleft. Therefore, in the post-acute phases of stroke, ibogaine functions as a neuromodulator, to stabilize glutamate production.

[0046] The events triggered by a CNS stroke begin with a collapse in energy production, affecting both the short and long term. This situation is associated with dysfunctions in oxidative phosphorylation processes and a marked decrease in ATP generation. Mainly, these repercussions are manifested in terms of energy. In the brain region affected by the interruptionof blood flow, the tissue continues to consume ATP, even though its production is impaired. This leads to a decrease in ATP concentrations and a consequent loss of neuronal homeostasis. Oxygen deprivation diverts glucose metabolism to anaerobic pathways, increasing lactic acid production and acidosis. This acidosis further inhibits oxidative phosphorylation, exacerbating the energy shortage. Low ATP concentrations prevent cells from performing vital functions; for example, the Na+ / K+ ATPase pump ceases to function properly, altering resting membrane potentials and causing anoxic depolarizations and cytotoxic edema. These phenomena mark the beginning of the ischemic cascade.

[0047] Ibogaine affects ATP concentration and enzymes associated with energy production. The use of ibogaine in erythrocytes under laboratory conditions caused an increase in ATP levels in blood plasma, without altering the membrane fluidity of these erythrocytes or modifying uric acid levels, as well as the function of antioxidant enzymes in cells, thus modifying the redox balance over time. Therefore, in the post-acute phases of stroke, ibogaine can help to restimulate the production of cellular energy.

[0048] Prolonged neuronal depolarization, such as occurs in CNS stroke, has been suggested to play a crucial role in the genesis of excitotoxic cell damage and death. This occurs through two mechanisms: the release of glutamate that entrains neighboring neurons and the inability to achieve adequate repolarization, which triggers cytotoxic edema and, in some cases, neuronal death.

[0049] Ibogaine has significant effects in inducing increased excitability and rapidity in the activation of parabrachial neurons, through depolarization, decreased rapid synaptic transmission dependent on non-NMDA receptors, involvement of dopamine receptor activation in its mechanisms of action (Kombian, S. B., Saleh, T. M., Fiagbe, N. I., Chen, X., Akabutu, J. J., Buolamwini, J. K., & Pittman, Q. J. (1997). Ibogaine and a total alkaloidal extract of Voacanga africana modulate neuronal excitability and synaptic transmission in the rat parabrachial nucleus in vitro. Brain research bulletin, 44(5), 603-610. https: / / doi.org / 10.1016 / s0361-9230(97)00284- 0). Therefore, in the post-acute phase of stroke, ibogaine functions as a membrane modulator, activating growth factors that can increase synaptic transmission and excitability of damaged cells.Treatment of Methods

[0050] In a preferred embodiment, the treatment requires initially loading the system with ibogaine, followed by maintenance using smaller dosages that are continued over a number of days. This loading can be achieved in one of three ways: through the administration of a flood dose, followed by microdosing; through the administration of mid-range dosages, followed by microdosing; or through a sustained period of microdosing.

[0051] In a preferred embodiment, the initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 3 to about 24 mg / kg, from about 5 to about 21 mg / kg, preferably from about 8 to about 18 mg / kg, preferably from about 10 to about 15 mg / kg, preferably from about 12 to about 14 mg / kg.

[0052] An initial dose of 13mg / kg, to is preferred, with an upper limit of 1200 mg total for the initial calculated flood dosage.

[0053] In some cases, during the process of administering a flood dose, one or more booster dosages of 100-600 mg (typically 200-400 mg) can be provided 12 hours or more before or after the flood in order to boost levels of noribogaine. This can be preferable in cases where the patient either felt less effect than desired from the medicine, or where dosing was interrupted for tolerability.

[0054] By combining these methods, in some cases the equivalent or greater than a single flood dose over a period of time can be provided for patients with high sensitivity or tolerability issues, and achieve similar or greater saturation of noribogaine. This involves the administration of a series of mid-range dosages, which are taken over a period of two or more days, avoiding peak saturation of ibogaine.

[0055] In a preferred embodiment, the microdose of ibogaine is selected from a dosing range of from about 8 to about 300 mg, from about 10 to about 200 mg, preferably from about 12 to about 150 mg, preferably from about 15 to about 80 mg, preferably from about 20 to about 60 mg.

[0056] In a preferred embodiment powdered ibogaine hydrochloride is compounded to the appropriate ratio with vitamins. In a preferred embodiment, a sodium ascorbate or calcium ascorbate form of Vitamin C is included in the composition. Preferably, capsules are filled with the mixture in bulk and bottled.Dosing Instructions

[0057] Microdosing preferably begins from 1-14 days, more preferably 1-3 days, after a flood dose or a series of mid-range doses.

[0058] Microdosing can be maintained for psychotherapeutic effect, and for increased exposure to ibogaine and noribogaine and resulting benefit to cellular function and CNS stroke symptoms. Patients can be coached that after 1-2 months they can choose to take breaks in the daily schedule of microdosing, including stopping dosages for 1-4, or 2-3 weeks in order to reduce any accumulation of tolerance to the medicine and also to self-evaluate their current status in regards to physical and mental symptoms. In these instances, patients are requested to keep a diary of dosage days for case studies.

[0059] Any changes to medication or health status may be discussed with the clinic physician.

[0060] Patients are directed to take one capsule daily in the morning. In cases where effects drop off or are not noticeable after 2 weeks, dosages can be tapered upward.

[0061] Patients are coached regarding potential tolerability, most of which are dose dependent. Dosing late in the day, and especially at night, can lead to sleep disturbances. Higher sensitivity to caffeine and other drugs can be noted. Medication contraindications should be closely monitored. Dosages that have more than the mildest psychoactive properties are typically unwanted for daily dosing.

[0062] Embodiments of the invention will be illustrated with reference to the following nonlimiting Examples which should not be used to construe or limit the scope of the invention.Patient A (“A”)

[0063] In May, 2023, an Ambio Life Sciences (“Ambio”) facility in Tijuana, Mexico, admitted A, a 45-year-old man seeking ibogaine treatment related to episodes of anxiety related to a transient ischemic attack (TIA) that he experienced over 4 years prior. Following the stroke, A experienced no residual motor impairment, but did suffer from daily panic attacks, some of which he described as catastrophic. Occasionally, during periods of stress, he experienced transient episodes of dizziness and instability, accompanied by subjective hemiplegic sensations.

[0064] Following the treatment (see Methodology below), A experienced no further panic episodes, and described no further episodes of dizziness.Patient B (“B”)

[0065] In November, 2023, B, a 38-y ear-old man with a military background contacted Ambio inquiring about ibogaine treatment. 2 years prior, in December, 2022, B was admitted for C5-C7 artificial disc replacement surgery for injuries related to blast exposure, which resulted in motor deficiencies on the left side of his body. On the operating table, B had an ischemic stroke and woke up paralyzed on the right side of his body, experiencing extreme nerve pain that passed from his neck through his trapezius to parts of his right arm.

[0066] Physiotherapy and pain management allowed B to regain some motor control. However, when B was admitted for treatment at Ambio he continued to experience insensitivity in his right leg and foot, resulting in gait instability, as well as baseline pain levels of 8-9 on a 10-point scale. This made it difficult for B to operate a vehicle without sudden jerky movements and hard braking.

[0067] Following ibogaine treatment (see Methodology below), B has not experienced nerve pain or sensitivity, even without the use of painkillers or muscle relaxers. Beginning on his second day after treatment, he experienced significant improvements in stability and sensitivity. This improvement in sensation has recovered his ability to drive, and he has experienced substantial improvements in gait.Methodology

[0068] The treatment that was conducted in each case included a loading dose (A: 1200mg, and B: 982mg) of ibogaine hydrochloride during an inpatient stay at an Ambio facility. The ibogaine used in treatment is produced semi-synthetically via voacangine that is extracted from Voacanga africana. Independent TLC analysis showed no impurities.Preparation and Dosing

[0069] Powdered ibogaine hydrochloride was administered in capsule form and divided into 3 to 5 (A: 4, B: 4) dosages. An initial test dose of 200-600mg (typically 400mg) was administered, followed by equal divisions of the remainder beginning after 30-90 minutes, and continuing then at 15-30-minute intervals. The intent is to ingest the complete initially calculated dose within a 2-hour window.Adjustments for Tolerability

[0070] Some patients are unable / unwilling to ingest the last measured dosage, or are so overwhelmed by the effects that it is deemed unnecessary by the facilitator.

[0071] Some patients feel little effect from the initial calculated dosage even after 3 hours or more. Between 2.5-3 hours we sometimes discuss a booster dosage for those who feel comfortable with a stronger effect. This additional dosage can range from 2 to 5 mg / kg. Additional dosages are sometimes preferred when we select the upper limit dosing of 1200mg. This dose is additional to the initial calculated dose, raising the overall dosage by weight.Evaluation

[0072] Patients were evaluated with electrocardiograms, blood work and a 20-panel urine drug screen. They were under constant cardiac monitoring for a minimum of 12 hours during high dose events, and were administered a metabolic assistance protocol that includes medications and IV therapies.

[0073] Follow-up evaluations were conducted by a psychologist over the phone, taking into consideration the anecdotal reports of each patient.OTHER EXAMPLESGait Recovery

[0074] The effect of both a vehicle and ibogaine gait recovery following a unilateral focal ischemic stroke of the hindlimb region in the motor cortex is assessed.

[0075] Kinetic gait analysis is performed before (day -2) and after (day 7, 14, 21, 28, 35, and 42) a modeled focal ischemic stroke in male C57BE6 mice. A photothrombotic stroke is produced by injecting mice will rose Bengal and then shinning a cool light on the surface of the skull above the hindlimb region of the left motor cortex. To assess the ability of ibogaine to reverse gait deficits, vehicle (NEOBEE; 100 pl) or ibogaine (40 mg / kg) is administered orally after the gait measurements of day 7.

[0076] Statistical comparisons between the vehicle and ibogaine treated animals is performed using a two-way repeated measures ANOVA followed Sidak’s multiple comparison tests for gait data from day 14-42.Brain Damage Repair

[0077] After the gait measurements on day 42, brain injury and metabolic enzyme, mitochondrial, and neurotrophic, and myelin-related gene expression, as well as neuronal cell numbers and axonal integrity are quantified in the affected hemisphere. Mice from the Gait Recovery study are humanely sacrificed with an overdose injection of pentobarbital (150 mg / kg) after the final gait measurements on DPI 42. The brain is removed, sectioned, and processed for histological analysis. Total RNA is extracted from the cortices of additional mice and used for the quantification of mRNA levels using RT-qPCR. Using LC-MS-MS, ibogaine and noribogaine levels in the plasma and cortex are measured in subgroups of mice 1, 4 and 24 hours after oral dosing with ibogaine.

[0078] Brain injury is assessed by counting Fluoro-Jade positive cells (damaged cells) in the affected cortex. Brain injury and repair is also assessed by counting immunolabelled oligodendrocyte progenitor cells, oligodendrocytes, and neurons. Computer assisted image analysis is used to quantify cells numbers. Statistical analysis will be performed using the Mann Whitney U test. Power analysis indicated that 6 mice / group will detect a predicted 50% difference between means with a standard deviation of 15% with 100% accuracy at alpha=0.05.

[0079] While this invention has been described with reference to illustrative embodiments and examples, the description is not intended to be construed in a limiting sense. Thus, various modifications of the illustrative embodiments, as well as other embodiments of the invention, will be apparent to the persons skilled in the art upon reference to this description. It is therefore contemplated that the appended claims will cover any such modifications and embodiments.

[0080] All publications, patients, and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by the reference in its entirety.

Claims

What is claimed is:

1. A method for treating CNS stroke and reducing associated disability in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of ibogaine, botanical iboga extract, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

2. The method defined in Claim 1, wherein the treatment comprises a loading dosage of ibogaine followed by a number of microdoses of ibogaine.

3. The method defined in Claim 2, wherein the loading dosage is composed of an initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 3 to about 24 mg / kg.

4. The method defined in Claim 2, wherein the loading dosage is composed of an initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 3 to about 24 mg / kg.

5. The method defined in Claim 2, wherein the loading dosage is composed of an initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 8 to about 18 mg / kg.

6. The method defined in Claim 2, wherein the loading dosage is composed of an initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 10 to about 15 mg / kg.

7. The method defined in Claim 2, wherein the loading dosage is composed of an initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 12 to about 14 mg / kg.

8. The method defined in Claim 2, wherein the loading dosage is composed of a series of mid-range doses of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 1 mg / kg to 8 mg / kg. Mid-range doses are generally considered to be dosages, less than a loading dose, which exhibit perceptual effects.

9. The method defined in Claim 2, wherein the loading dosage is composed of a series of mid-range doses of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 2 mg to 5 mg / kg.

10. The method defined in any one of Claims 2-11, wherein the microdose of ibogaine is selected from a dosing range of from about 8 to about 300 mg. Microdoses are generally considered to be dosages, less than a loading dose, which exhibit little or no perceptual effects.

11. The method defined in any one of Claims 2-11, wherein the microdose of ibogaine is selected from a dosing range of from about 10 to about 200 mg.

12. The method defined in any one of Claims 2-11, wherein the microdose of ibogaine is selected from a dosing range of from about 12 to about 150 mg.

13. The method defined in any one of Claims 2-11, wherein the microdose of ibogaine is selected from a dosing range of from about 15 to about 80 mg.

14. The method defined in any one of Claims 2-11, wherein the microdose of ibogaine is selected from a dosing range of from about 20 to about 60 mg.

15. The method defined in any one of Claims 2-16, wherein the microdose of ibogaine is administered daily.

16. The method defined in any one of Claims 2-16, wherein the microdose of ibogaine is administered as a loading dosage, and / or as a maintenance dosage, for a duration of from about 1 month to about 5 years.

17. The method defined in any one of Claims 2-16, wherein the microdose of ibogaine is administered as a loading dosage, and / or as a maintenance dosage, for a duration of from about 2 months to about 4 years.

18. The method defined in any one of Claims 2-16, wherein the microdose of ibogaine is administered as a loading dosage, and / or as a maintenance dosage, for a duration of from about 2.5 months to about 3 years.

19. The method defined in any one of Claims 2-16, wherein the microdose of ibogaine is administered as a loading dosage, and / or as a maintenance dosage, for a duration of from about 3 months to about 2 years.

20. The method defined in any one of Claims 2-16, wherein the microdose of ibogaine is administered as a loading dosage, and / or as a maintenance dosage, for a duration of from about 4 months to about 1 year.

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