Ibogaine treatment for lesion reduction and neural structural changes

Abstract

There is described a method for inducing lesion (preferably brain lesion) reduction in a patient in need thereof and / or Apparent Diffusion Coefficient (ADC) values (suggesting remyelination and reduced inflammation). The method comprises administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

Description

IBOGAINE TREATMENT FOR LESION REDUCTION AND NEURAL STRUCTURAL CHANGESCROSS-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 / 724,722, filed November 25, 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 multiple sclerosis in a subject. In another of its aspects, the present invention relates to a pharmaceutical composition useful for treatment of multiple sclerosis in a subject. In yet another of its aspects, the present invention relates to a pharmaceutical composition useful for treatment of multiple sclerosis while reducing associated lesions in a subject.DESCRIPTION OF THE PRIOR ART

[0003] Multiple sclerosis (MS) is generally known as an autoimmune disease of the central nervous system with both autoimmune and neurodegenerative features. It affects approximately 400,000 persons in the United States and 1.2 million persons worldwide. It is a major cause of neurological disability in young adults, who usually present with a relapsing, remitting pattern of neurologic involvement and progress to a chronic phase with increasing difficulty in ambulation and coordination.

[0004] Studies have shown that nearly fifty percent of MS patients require an assistive device to walk after a decade of disease. Therefore, the societal impacts of both direct medical and indirect economic costs of MS are enormous and often imposed on young families.

[0005] Currently used drugs / agents for MS treatment either modify or suppress the body's immune system. They have been shown to modestly reduce neurological relapses of the disease and, in some instances, incompletely slow the progression of neurological disability.

[0006] In addition, drugs / agents for MS treatment have not been reported to reduce the lesions associated with MS.

[0007] However, the vast majority of currently used drugs / agents for MS are variously limited by incomplete efficacy, side effects and medical risks - e.g., injection site reactions, including skin necrosis; flu-like symptoms; depression; psychosis; hypersensitivity; allergic reactions; cardiac and other organ toxicity from diabetes mellitus; cataracts; bone necrosis; serious and life threatening opportunistic infections, and risk of malignancy. The existence of these side effects and risks precludes the use of these drugs in many MS patients.

[0008] Various other details concerning the state of the art may be found in the Examples portion of the present application.

[0009] Thus, there is a pressing need for therapeutic approaches / agents that are safe, efficacious, well- tolerated, and which can be administered more conveniently. Ideally, such a therapeutice approach / agent would also concurrently reduce lesions and / or induce a neural structural change in a patient, particularly a patient diagnosed with multiple sclerosis.SUMMARY OF THE INVENTION

[0010] It is an object of the present invention to obviate or mitigate at least one of the above- mentioned disadvantages of the prior art.

[0011] It is another object of the present invention for inducing lesion (preferably brain lesion) reduction and / or neural structural change in a patient.

[0012] Accordingly, in one of its aspects, the present invention provides a method for inducing lesion (preferably brain lesion) reduction in a patient in need thereof and / or Apparent Diffusion Coefficient (ADC) values (suggesting remyelination and reduced inflammation), comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

[0013] In another of its aspects, the present invention provides a method for inducing neural structural changes (e.g., cortical and subcortical alterations, particularly in regions associated with pain and emotional processing) in a patient, comprising administering to the patient atherapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.BRIEF DESCRIPTION OF THE DRAWINGS

[0014] Embodiments of the present invention will be described with reference to the accompanying drawings, wherein like reference numerals denote like parts, and in which Figures 1-3 illustrate various of the results reported in the Examples below.DETAIEED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0015] Various terms used throughout this specification are intended to have the following meanings.

[0016] By "ameliorate" is meant decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease.

[0017] 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.

[0018] In this specfication, "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 which is 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.

[0019] 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.

[0020] 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.

[0021] 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.

[0022] 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.

[0023] 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.

[0024] 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

[0025] The present invention provides methods to reduce lesions and / or induce a neural structural change in a patient, particularly a patient diagnosed with multiple sclerosis which comprises administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of the formulae (e.g., ibogaine and ibogaine analogs) herein to a subject (e.g., a mammal such as a human). Thus, one embodiment is a method to reduce lesions and / or induce a neural structural change in a patient diagnosed with multiple. The method includes the step of administering to the mammal a therapeutic amount of an amountof ibogaine or an ibogaine analog sufficient to treat the disease or disorder or symptom thereof, under conditions to reduce lesions and / or induce a neural structural change in a patient, particularly a patient diagnosed with multiple sclerosis.

[0026] 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.

[0027] 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).

[0028] 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.

[0029] 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).

[0030] 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., any target 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 multiple sclerosis, 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.

[0031] 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 tomonitor the course of disease or the efficacy of the therapy. In certain preferred embodiments, a pre-treatment 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.

[0032] The invention further relates to methods for treatment and / or prevention of multiple sclerosis, including symptoms associated with multiple sclerosis, 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.

[0033] 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 MS, mice, rats, rabbits, nonhuman primates, such as monkeys, are also within the scope of the invention (e.g. experimental allergic encephalomyelitis (EAE)).

[0034] Herein, "multiple sclerosis" is used as per the accepted textbook definition in the field (Handbook of Multiple Sclerosis. 3rd Edition. Edited by Stuart D. Cook. Marcel Dekker, Inc., 2001). Diagnostic criteria used to identify a subject with multiple sclerosis would be apparent to a person of skill in the art. For example, a skilled individual would appreciate that clinically defined multiple sclerosis is based on two attacks of neurological dysfunction separated in time and space. More recent diagnostic criteria for MS include the presence of characteristic areas on cranial or cervical magnetic resonance imaging (MRI).

[0035] Multiple sclerosis frequently begins in young adulthood with episodic attacks of neurological dysfunction - e.g., visual loss, sensory alterations, motor weakness, ataxia, etc. These subjects are within the scope of the present invention. Although the precise cause of multiple sclerosis is largely unknown, it is thought to result from an autoimmune reaction to the protein component of the myelin that forms a sheath-like covering around nerve axonsand enhances electrochemical signaling in the central nervous system. Examples of such protein components include, but are not limited to, myelin basic protein, proteolipid protein and myelin oligodendrocyte glycoprotein.

[0036] Common symptoms of multiple sclerosis and 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.

[0037] Certain known subtypes of multiple sclerosis exist that are generally defined by the profile of symptoms exhibited by the subject, including onset, duration, and patterns of neurological dysfunction and / or disability. Subjects suffering from MS subtypes are also within the scope of the invention.

[0038] Relapses of multiple sclerosis are discrete occurrences of a subtype of multiple sclerosis known as relapsing remitting multiple sclerosis (RRMS) and occur less often in secondary progressive multiple sclerosis (SPMS). As used herein, a "relapse" is defined as the onset of new or worsening neurological symptoms usually lasting at least 48 hours in the absence of any precipitating factor, such as fever orinfection. Subjects suffering from relapses or RRMS are within the scope of the present invention.

[0039] Relapses of multiple sclerosis, include but are not limited to, symptoms which may occur alone or in combination of increased or new onset numbness in the trunk or limbs, weakness of the trunk or limbs, imbalance, difficulty walking, reduced or double vision, pain of the face, trunk or extremities, difficulty in urination or bowel movements, sexual dysfunction, cognitive difficulties such as confusion, depression, psychosis or memory loss, vertigo or dizziness, fatigue, and cramps or spasms.

[0040] Subject exhibiting these symptoms are within the scope of the present invention.

[0041] The goal of treatment of relapses is to stop the autoimmune process associated with the relapse and / or to prevent or minimize residual neurological damage associated withincomplete remission, which occurs in a high percentage of patients. There is a significant risk of permanent and severely disabling neurological disability over time, particularly if the disease enters a chronic progressive phase after a relapsing remitting phase (CPMS). Ten percent of patients never experience a relapsing phase prior to a progressive phase and this is termed primary progressive multiple sclerosis (PPMS). There is also a risk that untreated or uncontrolled relapses lead to a state of SPMS, in which progressive neurological disability, including dementia, chronic vertigo, fatigue, visual impairment, motor weakness, sensory disturbances, bladder and bowel dysfunction, ambulation difficulties or non- ambulation, ataxia and pain occur in the absence or reduced frequency of discrete attacks. SPMS and PPMS respond poorly to current drug treatment. Subjects with CPMS and PPMS are also within the scope of the invention.Ibogaine

[0042] Ibogaine has been used as a botanical preparation from the root bark of iboga tabemathe for over 100 years both as a crude preparation, 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 is limited due to potentially adverse side effects. For example, in larger dosages ibogaine exhibits stimulant and hallucinogenic properties, and in addition, can induce temporary ataxia and tremors. At conventional doses, ibogaine causes these side effects in a majority of patients receiving treatment.

[0043] 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. Lotsof and Wachtel, Manual for Ibogaine Therapy: Screening, Safety, Monitoring & Aftercare (2d revision, 2003), accessed at www.ibogaine.desk.nl / manual.html; Hoelen, et al. New Engl. J. Med. 360(3), 308 (2009), which is incorporated herein by reference in its entirety for all of its methods, compositions and teachings. See also the Clinical Guidelines for Ibogaine Assisted Detoxification: https: / / ibogaineguidelines.com.

[0044] "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 Tabemanth 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 Tabemtanthe iboga, or other alkaloids found present in it, including ibogamine, ibogaline, tabemanthine, coronoradine, voacangine, etc.Treatment Methods

[0045] In a preferred embodiment, the treatment comprises an initial flood dose of ibogaine followed by a daily microdose for a number of days after the initial flood dose.

[0046] 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.

[0047] At 13mg / kg, to is preferred toan upper limit of 1200 mg total for the initial calculated flood dosage.

[0048] In some cases, 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.

[0049] 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.

[0050] 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.

[0051] 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

[0052] Microdosing preferably begins from 1-14 days, more preferably 1-3 days, after a flood dose in order to benefit from and boost noribogaine saturation.

[0053] Microdosing can be maintained for psychotherapeutic effect, and for increased exposure to ibogaine and noribogaine and resulting benefit to lesion reduction over time. 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 physican and mental symptoms. In these instances, patients are requested to keep a diary of dosage days for case studies.

[0054] Any changes to medication or health status may be discussed with the clinic physician.

[0055] 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.

[0056] 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 most mild psychoactive properties are typically unwanted for daily dosing.

[0057] Embodiments of the invention will be illustrated with reference to the non-limiting Examples which should not be used to construe or limit the scope of the invention.EXAMPLES

[0058] Introduction

[0059] Ibogaine, is a naturally occurring indole alkaloid with complex neuropharmacology and strong oneirogenic (“waking dream generating”) properties. Although most widely discussed as an aid to mitigating withdrawal and cravings from opioids and other drugs (1,2,3), ibogaine has recently garnered attention for its potential to alleviate symptoms associated with traumatic brain injury (4), neuropathic pain (5), and other neurodegenerative conditions.

[0060] Ibogaine’s physiological effects appear to involve multiple mechanisms. Its interaction with NMD A, sigma-2, and opioid receptors influence neural activity and plasticity (1,6). Upregulation of both brain-derived neurotrophic factor (BDNF) and glial cell-derived neurotrophic factor (GNDF) promotes neuronal survival and plasticity (7,8,9). Reduction of pro-inflammatory cytokines decreases neuroinflammation (10). Improvements in cellular respiration may contribute to structural changes in neuronal cells (11,12). The upregulation of genes and proteins may contribute to the process of remyelination (13).

[0061] Multiple sclerosis (MS) is a chronic demyelinating disease characterized by neuroinflammation, axonal damage, and progressive neurological deficits (14). Standard treatments aim to modulate immune responses and slow disease progression but often have limited efficacy and significant side effects (15).

[0062] MS diagnosis relies on a combination of clinical evaluations and imaging studies. Cortical thickness analysis and diffusion-weighted imaging (DWI) are valuable neuroimaging tools for studying MS-related brain changes. Cortical thickness changes may reflect alterations to neurocircuitry, while DWI measures water diffusion to assess tissue integrity. Increased Apparent Diffusion Coefficient (ADC) values may suggest demyelination and axonal damage, whereas decreased ADC values may indicate improved neural integrity and reduced inflammation (16,17,18,19,20,21,22).

[0063] The present case report demonstrates the treatment effects of ibogaine on two patients who initially sought ibogaine for other reasons, but also had pre-existing diagnoses of MS. To our knowledge, this is the first documented case report suggesting neuroregenerative effects of ibogaine in human MS patients.

[0064] Case Presentation

[0065] Patient A

[0066] In February, 2023, an Ambio Life Science (“Ambio”) ibogaine treatment facility in Tijuana, Mexico received a 41 -year-old male special forces veteran (“PA”) who was diagnosed with relapsing-remitting MS (RRMS), PTSD, MDD, and a TBI sustained ten years prior. He attended the program once previously, in September, 2022, at which time he suffered from vertigo believed to result from high alcohol intake. After his first treatment, vertigo symptoms resolved in the absence of alcohol consumption, only to return 2 months later, leading to his RRMS diagnosis.

[0067] At intake, PA’s symptoms included progressive mobility impairment, coordination difficulties, some bladder control issues, bradypsychia, short-term memory deficits, and strong vertigo sensations every five to ten minutes. Emotional stress from relationship dissatisfaction was an additional factor influencing his overall health. His primary care physician prescribed dimethyl fumarate and Vitamin D to manage MS symptoms one month prior, but progressive neurological decline continued. MRI revealed a large lesion in the right posterior parietal lobe, affecting cortical and subcortical white matter near the intraparietal sulcus (Figure 1).

[0068] Patient B

[0069] Also in February 2023, Ambio received a 44-year-old female (“PB”) who was diagnosed with secondary progressive MS (SPMS) in 2018, as well as complex PTSD (CPTSD) from childhood trauma and a recent divorce following 17 years of marriage. Upon arrival, she exhibited severe muscle spasticity, hypotrophic extremities, difficulties with bladder and bowel control, and strong but infrequent attacks of vertigo. Although she could transfer herself using wall-mounted arm supports, she required a wheelchair for mostactivities. As of 4 months prior to intake, she was diagnosed “exercise intolerant,” precluding physiotherapy for more than 5 to 10 minute increments.

[0070] PB became confined to her mobility system after the installation of an intrathecal baclofen pump in 2019, which reduced the painful muscle spasticity that had previously allowed her to walk.

[0071] She had taken glatiramer, high doses of Vitamin D, and also consumed cannabis on a regular basis to control muscle spasticity since 2018. Despite short-term success with ketamine therapy to try to control chronic pain, she terminated treatment infusions one year prior.

[0072] Methodology

[0073] Clinical Protocol

[0074] Both patients underwent an ibogaine treatment protocol at Ambio, preceded by a physical intake, full metabolic panel, and electrocardiogram. 24-hour medical staff collected vitals every 30 minutes during waking hours. A patent-pending co-therapy protocol, including pre-treatment magnesium and vitamin infusions as well as post-treatment metabolic support was administered around a “flood dose,” or “loading dose” (PA: 1200mg; PB: 500mg), during which time patients remained under constant cardiac monitoring to screen for arrhythmias including bradycardia.

[0075] PB’s dosage was adjusted to accommodate an acute increase in her existing muscle spasticity. Once discharged, both patients continued a “microdose,” or “maintenance dosing” regimen (20mg / day).

[0076] The Multiple Sclerosis Quality of Life Index (MSQLI) and Hauser Ambulation Index (HAI) were used to quantify subjective changes and clinical observations.

[0077] Imaging Analysis

[0078] Diffusion-weighted imaging (DWI) and anatomical structural MR images were acquired for each patient within two months prior to arrival and three months after treatment.These images were used to generate cortical thickness measurements and apparent diffusion coefficient (ADC) maps.

[0079] DWI Preprocessing

[0080] DWI data underwent initial preprocessing steps. Brain extraction was performed on the trace image using BET2 (Brain Extraction Tool) of the FSL software library (23). The resulting brain mask was applied to the calculated ADC image to create a brain-extracted ADC.

[0081] Cortical Parcellation and Subcortical Segmentation

[0082] Cortical surface reconstruction and cortical thickness measurements were performed using the recon-all-clinical pipeline from FreeSurfer, optimized for heterogeneous clinical MRI scans (24). The pipeline incorporates machine learning-based segmentation methods, such as SynthSeg (25,26) and SynthSR (27), to enhance robustness and reliability. SynthSeg allows for segmentation of brain MRI scans of any contrast and resolution, making it suitable for comparative analysis of heterogeneous clinical brain scans. SynthSR uses superresolution to convert anatomical scans of varying contrasts into T1 -weighted images suitable for cortical segmentation. The Desikan-Killiany atlas (28) was employed for cortical parcellation.

[0083] Lesion Segmentation

[0084] Lesion segmentation and quantification was performed manually with the 3D Slicer software suite (29). The lesion was outlined on the T1 anatomical MR image at each slice (30) to create a detailed lesion segmentation mask as the measurement region of interest (ROI). The lesion ROI is then subsequently projected to its intra-subject DWI space for ADC quantification.

[0085] Anatomical and DWI Registration

[0086] To align the anatomical (T1 or T2) images with the DWI space, a multi-stage registration process was implemented using ANTs (Advanced Normalization Tools) (31). The process involved the following steps: 1. Intra-subject longitudinal Rigid registration in anatomical space, from intrasubject time 2 to time 1. Diffeomorphic registration (SyNalgorithm) from the DWI space to the anatomical space for each time point (32,33). The ROIs for both cortical and lesion segmentations were then projected from anatomical to DWI space for ADC quantification.

[0087] Clustering Analysis

[0088] A Gaussian Mixture Model was used to perform clustering analysis on interhemispheric cortical thickness percentage changes to identify patterns of regional alterations and possible changes in neurocircuitry.

[0089] Results

[0090] Clinical Observations

[0091] Patient A

[0092] One day after treatment, PA subjectively noted a resolution of MS symptoms, including motor and bladder issues. 2 months post-treatment, MSQLI fatigue subscores dropped 92%. Bladder control issues completely resolved. The physical components summary score increased 24%, and mental components summary score improved by 42%. Despite previous challenges walking because of an inability to coordinate foot movement, PA later reported participation in a 200 mile ultramarathon. One year after this second treatment episode, he still had not experienced any remission of vertigo.

[0093] Patient B

[0094] Despite acute increases in muscle spasticity under ibogaine’s effects, PB reported reductions in spasticity post-treatment. HAI scores improved from 8 (“restricted to wheelchair”) at baseline, to 7 (“walking limited to several steps with bilateral support”) immediately upon discharge, a change sustained at month 2 follow-up. PB increased the duration of physiotherapy from 10 minutes to 1 hour, and reported continued gradual improvement 2 years later. MSQLI scores dropped 73% for chronic pain, and 29% for fatigue. Bladder control score dropped from 5 to 3, and bowel control dropped from 6 to 2. Physical components summary score increased 38%, while mental components summary improved 22%.

[0095] Brain Imaging

[0096] Patient A

[0097] Post-treatment analysis revealed a 71% reduction in lesion volume (from 1,659.8 mm3to 480.5 mm3) and a 35.6% decrease in mean ADC (from 2,756.3 x 106mm2 / s to 1,774.2 x 106mm2 / s), suggesting reduced extracellular diffusion (Figure 1).

[0098] Regions associated with emotional and cognitive processing exhibited cortical thinning, including the left rostral and caudal anterior cingulate cortices (6.94% and 5.23%, respectively), left frontal pole (4.66%), and right precuneus (4.01%). In contrast, cortical thickening was noted in the right cuneus (4.43%) and entorhinal cortex (3.67%), with asymmetric decreases in the left cuneus (3.38%) and entorhinal cortex (1.96%) (Figure 2).

[0099] ADC changes varied across regions. Notable reductions were seen in the left lateral orbitofrontal cortex (4.96%) and right temporal pole (4.40%). Significant ADC increases included the right rostral middle frontal cortex (25.77%) and paracentral lobule (16.20%), and the left entorhinal cortex (11.13%) (Figure 2).

[0100] Ventricular volume decreased bilaterally (-31%), with asymmetrical ADC changes (left -25.02%; right: +4.92%). The left pallidum (48.3%) and amygdala (25.12%) increased in volume, while hippocampal changes were asymmetric (right: +20.49%; left: -11.08%). These changes suggest hemispheric compensatory responses.

[0101] Gaussian Mixture Model analysis of cortical thickness changes identified three clusters (Figure 3). Regions associated with cortical thinning included areas involved in emotional processing, such as the anterior cingulate cortex and insula. Regions showing symmetrical thickening or stability included areas related to memory and sensory integration, such as the middle temporal gyri and posterior cingulate. Asymmetrical changes were observed in regions like the cuneus and entorhinal cortices, indicating differential hemispheric responses.

[0102] Patient B

[0103] Cortical thinning was observed in several regions, including the right transverse temporal cortex (-9.17%) and left (-6.32%), and the right postcentral cortex (-4.10%) and left(-3.39%). Asymmetrical changes were notable in the entorhinal cortex, where the right decreased (-4.82%) and the left increased (+2.4%), and in the rostral anterior cingulate, where the left decreased (-4.82%) and the right increased (+6.01%). Conversely, cortical thickening was evident in regions such as the right isthmus cingulate (+5.52%) and left lingual cortex (+8.10%) (Figure 2).

[0104] ADC changes varied across regions. Decreases included the left pars orbitalis (- 5.72%), right pericalcarine cortex (-5.30%), and left lateral occipital cortex (-4.92%). In contrast, ADC increases were more prominent, such as in the left paracentral lobule (+22.10%), right paracentral lobule (+14.8%), left posterior cingulate cortex (+16.78%), and right posterior cingulate cortex (+8.46%). Other notable increases included the right frontal pole (+14.34%), left entorhinal cortex (+15.17%), and caudal anterior cingulate (left: +13.27%, right: +10.73%) (Figure 2).

[0105] Subcortical volume changes were also significant. The left and right lateral ventricle volumes decreased (-15.73% and -14.2%, respectively), while the right inferior lateral ventricle volume increased (+34.09%) as the left decreased (-5.74%). Asymmetrical changes were seen in the amygdala, with left volume decreasing (-9.51%) and right increasing (+20.19%), and in the accumbens area, with left volume increasing (+16.67%) and right decreasing (-16.47%). Increased volume was observed in the ventral diencephalon (right: +24.63%, left: +14.18%), pallidum (left: +13.96%, right: +12.02%), and putamen (left: +7.3%, right: +13.49%). Although caudate volume remained unchanged, ADC increased on both sides (left: +9.33%, right: +17.68%) (Figure 2).

[0106] Clustering analysis identified distinct patterns of cortical thickness changes (Figure 3). Regions with symmetrical thinning included clusters 1 and 4, encompassing areas associated with motor and executive functions, such as the paracentral lobules, postcentral gyrus, and transverse temporal cortex. These changes may reflect synaptic pruning and network optimization. Regions with symmetrical thickening, such as cluster 0, involved areas related to memory and executive functions, including the temporal pole and lateral orbitofrontal cortex. Asymmetrical left-side thickening and right-side thinning (cluster 2) were observed in memory and visual processing regions, including the entorhinal cortex, fusiform gyrus, and parahippocampal gyrus, possibly indicating neurogenesis and enhanced connectivity. Conversely, right-side thickening and left-side thinning (clusters 3 and 5) wereprominent in regions associated with emotional regulation, including the anterior and isthmus cingulate cortices and medial orbital frontal cortex, suggesting differential hemispheric responses in emotional networks.

[0107] Discussion

[0108] Patients A and B both demonstrated significant cortical and subcortical neuroplastic changes following treatment, highlighting ibogaine’s potential in promoting adaptive neural remodeling. While the regions affected varied based on individual clinical presentations, the overarching neuroimaging patterns underscore ibogaine’s influence on pain, emotional regulation, cognitive processing, and motor function.

[0109] For Patient A (PA), a dramatic reduction in lesion volume and decreased ADC values may suggest possible remyelination and reduced extracellular space due to diminished inflammation or edema (20). These changes likely reflect improved cellular density, myelin integrity, and enhanced tissue function (17). PA also exhibited cortical thinning in the anterior cingulate cortex (ACC) and frontal pole, possibly associated with improved emotional regulation, as thinning in these areas may optimize neural circuitry through synaptic pruning (34). Conversely, cortical thickening in the posterior cingulate cortex (PCC) and temporal regions indicated potential neurogenesis or enhanced connectivity, which may support improved memory and sensory processing (33). Subcortical changes, such as decreased ADC in the hippocampus and amygdala, suggested enhanced tissue integrity, correlating with better emotional and memory processing. These findings aligned with PA’s significant improvements in mental health and cognitive function, emphasizing ibogaine’s impact on emotional and cognitive neurocircuitry.

[0110] Patient B (PB) similarly exhibited cortical and subcortical changes, with cortical thinning in motor regions likely reflecting synaptic pruning of maladaptive pathways, facilitating improved motor coordination. Cortical thickening in the entorhinal cortex and fusiform gyrus suggested enhanced neuroplasticity, potentially improving cognitive and visual processing. Subcortical ventricular alterations implied reduced neuroinflammation, contributing to symptom improvement. Clustering analysis revealed coordinated neuroplastic changes in motor and cognitive networks, aligning with PB’s marked reductions in pain and enhanced physical functioning.

[0111] Despite these differences, both patients shared common neuroplastic adaptations in emotional and affective neurocircuitry, particularly in regions such as the ACC, underscoring ibogaine’s role in modulating pain and emotional regulation networks (35). PA’s dramatic decrease in lesion volume and markers of inflammation were likely influenced by his diagnosis of RRMS, a less severe condition compared to PB’s SPMS, which may explain his greater degree of symptom remission and observed MR imaging improvements.

[0112] In both patients, clustering analyses highlighted that ibogaine facilitated coordinated changes across distinct neural networks, tailored to their individual pathologies. These findings suggest that ibogaine’s therapeutic effects are not only wide-ranging but also individualized, supporting its role in promoting adaptive neuroplasticity and clinical recovery.

[0113] Potential Mechanisms of Regional Changes

[0114] Remyelination is suggested by the lesion reduction and ADC decreases observed in Patient A, which may improve neural conductivity and reduce symptoms (36). Synaptic pruning may be responsible for the cortical thinning in specific regions, enhancing network efficiency and contributing to functional improvements (34). Neurogenesis or dendritic growth could be indicated by the cortical thickening and ADC increases, which may enhance connectivity and cognitive function. Additionally, decreased ADC in ventricles and subcortical areas may reflect reduced inflammation and edema, contributing to symptom relief

[0115] While cortical thinning is generally linked to atrophy, it may also represent adaptive changes in the context of neuroplasticity. Synaptic pruning can enhance neural network efficiency, potentially leading to functional improvements despite reduced cortical thickness. This process is essential during development and may be recapitulated during neurorehabilitation.

[0116] Neurocircuitry Involved

[0117] The modulation of pain pathways is suggested by changes in the anterior cingulate cortex, insula, thalamus, and prefrontal cortex, which may contribute to reduced pain perception in both patients. Alterations in the cingulate cortex and frontal regions mayenhance emotional processing, reducing symptoms of depression and anxiety. Remodeling in the precentral and postcentral gyri and paracentral lobules in Patient B may improve motor function and coordination. Furthermore, changes in the hippocampus, entorhinal cortex, and temporal regions may enhance memory processing and cognitive function.

[0118] Alterations in the PCC and ACC may suggest modulation of the DMN. For PA, cortical thickening in the PCC may enhance DMN connectivity, improving cognitive functions like memory and self-awareness. For PB, changes in the PCC and ACC may alter DMN activity, reducing maladaptive rumination and pain perception. Modulation of the DMN may contribute to symptom relief in MS patients by improving functional connectivity and network efficiency.

[0119] Conclusion

[0120] These case studies suggest that ibogaine may induce neuroplastic and perhaps neuroregenerative changes in MS patients. The cortical and subcortical changes observed may represent adaptive processes contributing to clinical improvements. Modulation of the neurocircuitry related to pain and motor function may underlie these effects.

[0121] Supplementary Methods

[0122] Imaging Protocol

[0123] Patient A

[0124] The TI -weighted structural images were acquired using a 3D Magnetization Prepared Rapid Gradient Echo (MPRAGE) sequence on a 1.5T Siemens MAGNETOM Aera scanner. The acquisition employed a non-linear gradient correction and adaptive coil combination method using a 20-channel head and neck coil. The sequence parameters were as follows: TR = 2200 ms, TE = 2.98 ms, TI = 900 ms, flip angle = 15°, field of view = 100%, matrix size = 256 x 256, slice thickness = 1 mm, and in-plane phase-encoding direction = row. The images were obtained with GRAPPA parallel imaging (acceleration factor = 2) and 20% phase oversampling.

[0125] Diffusion-weighted images were acquired using a readout-segmented echo-planar imaging (rs-EPI) sequence, known as RESOLVE (Readout Segmentation Of Long Variable Echo-trains), on a 1.5T Siemens MAGNETOM Aera scanner. The images were obtained using a 20-channel head and neck coil, with adaptive coil combination. The sequence parameters were as follows: TR = 5700 ms, TE = 60.18 ms, flip angle = 180°, field of view = 100%, matrix size = 160 x 160, slice thickness = 5 mm, slice gap = 1.75 mm, and number of slices = 25. The diffusion-encoding scheme was monopolar, with a b-value of 1000 s / mm2Trace-weighted images were derived from the original diffusion-weighted data. GRAPPA parallel imaging (acceleration factor = 2) was employed. The effective echo spacing was 0.18 ms, with a total readout time of 28.62 ms. Fat suppression and 2D distortion correction were applied.

[0126] Patient B

[0127] 3D FLAIR images were acquired on a 1.5T Siemens Aera MRI scanner. The images were acquired using a 20-channel head and neck coil with adaptive combine coil combination method. The sequence employed a T2-weighted turbo spin-echo (TSE) acquisition with variable flip angle (VFL) and inversion recovery preparation. Specific parameters included: TR = 5000 ms, TE = 335 ms, TI = 1600 ms, flip angle = 120°, and 1 mm isotropic resolution. The acquisition matrix was 256 x 220 x 192 (sagittal orientation), with 98% phase resolutionand 87.5% phase field-of-view. GRAPPA parallel imaging was used with an acceleration factor of 2. The echo train length was 214, and the receiver bandwidth was 590 Hz / pixel. Fat suppression was applied.

[0128] Diffusion-weighted images were acquired on a 1.5T Siemens Aera MRI scanner using a single-shot echo-planar imaging (EPI) sequence. The images were obtained using a 20- channel head and neck coil with adaptive combine coil combination method. The protocol parameters were as follows: TR = 6300 ms, TE = 90 ms, flip angle = 90°, b-value = 1000 s / mm2, and 3 mm slice thickness with 0.3 mm gap. The acquisition matrix was 128 x 128, reconstructed to 256 x 256, with a 100% field of view and 2 averages. Parallel imaging (GRAPPA) was employed with an acceleration factor of 2. The diffusion-encoding scheme was bipolar. Fat suppression was applied, and partial Fourier (factor 0.75) was used. The effective echo spacing was 0.39 ms, with a total readout time of 99.45 ms. Trace-weighted images were derived from the original diffusion-weighted data.

[0129] ADC Map Calculation

[0130] Apparent Diffusion Coefficient (ADC) maps were calculated using the following equation:ADC _ 1..IS.) - l..(S.)x 10« bWhere So is the signal intensity in the bO image, Sb is the signal intensity in the trace- weighted image, and b is the b-value used for the trace-weighted image. The resulting ADC values are expressed in units of unrims.

[0131] Anatomical and DWI Registration

[0132] To align the anatomical (T1 or T2) images with the DWI space, a multi-stage registration process was implemented using ANTs (Advanced Normalization Tools) \cite{avants2011reproducible}. The process involved the following steps: 1. Longitudinal Rigid registration in T1 space, from intrasubject time 2 to time 1. Diffeomorphic registration (SyN algorithm) from the DWI space to the T1 space within each subject for each time point.

[0133] For intra-subject anatomical alignment \cite{chen2016merged}, we employed a rigid transformation model with a gradient step length of 0.1, using Mutual Information as the similarity metric with 32 histogram bins. This registration used four resolution levels (shrink factors: 8, 4, 2, 1; smoothing sigmas: 3, 2, 1, 0 voxels) with 1000, 500, 250, and 100 iterations respectively, converging at a threshold of le-6 with a convergence window of 10.

[0134] For the DWI to anatomical space registration, we utilized a two-step approach. First, an affine transformation was computed using Mutual Information as the similarity metric, with 32 histogram bins. This step employed a multi-resolution strategy with five levels (shrink factors: 5, 4, 3, 2, 1; smoothing sigmas: 4, 3, 2, 1, 0 mm), each running for 10,000 iterations. Subsequently, a deformable Symmetric Normalization (SyN) transformation was applied, using cross-correlation as the similarity metric with a 3x3x3 neighborhood. The SyN registration used three resolution levels (shrink factors: 3, 2, 1; smoothing sigmas: 2, 1, 0 mm) with 50, 35, and 15 iterations respectively. The gradient step size for the SyN transformation was set to 0.15 with a total of 3 time points.

[0135] All transformations were performed utilizing B-spline interpolation for structural images and nearest neighbor interpolation for region-of-interest (ROI) projections to preserve label integrity.

[0136] GMM Clusters

[0137] Patient A

[0138] Cluster 0: bankssts, caudalanteriorcingulate, frontalpole, lateralorbitofrontal, parahippocampal, parsorbitalis, postcentral, precentral, superiorparietal

[0139] Cluster 1: inferiortemporal, isthmuscingulate, middletemporal, temporalpole, transversetemporal

[0140] Cluster 2: cuneus, entorhinal

[0141] Cluster 3: medialorbitofrontal, rostralmiddlefrontal, superiorfrontal, supramarginal

[0142] Cluster 4: fusiform, inferiorparietal, lateraloccipital, parsopercularis, pericalcarine

[0143] Cluster 5: parstriangularis, precuneus

[0144] Cluster 6: lingual, posteriorcingulate

[0145] Cluster ?: rostralanteriorcingulate

[0146] Cluster 8: caudalmiddlefrontal, insula, paracentral, superiortemporal

[0147] Patient B

[0148] Cluster 0: inferiortemporal, lateralorbitofrontal, parstriangularis, temporalpoleCluster 1: caudalmiddlefrontal, middletemporal, paracentral, parsopercularis, postcentral, precentral, superiorfrontal, superiorparietal, supramarginal, transversetemporal

[0149] Cluster 2: bankssts, cuneus, entorhinal, fusiform, inferiorparietal, lingual, parahippocampal, parsorbitalis, precuneus, superiortemporal

[0150] Cluster 3: rostralanteriorcingulate

[0151] Cluster 4: caudalanteriorcingulate, frontalpole, insula, isthmuscingulate, lateraloccipital, medialorbitofrontal, pericalcarine, posteriorcingulate, rostralmiddlefrontal

[0152] 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 persons skilled in the art upon reference to this description. It is therefore contemplated that the appended claims will cover any such modifications or embodiments.

[0153] All publications, patents 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 reference in its entirety.References Referred to in Examples Alper, Kenneth R. Ibogaine: a review. 2001 Brown, Thomas K. Ibogaine in the treatment of substance dependence. Curr Drug Abuse Rev. 2013 Mar;6(l):3-16 Belgers, M, Leenaars, M, Homberg, J. et al. Ibogaine and addiction in the animal model, a systematic review and meta-analysis. Transl Psychiatry 2016;6, e826 Cherian, Kirsten N, Keynan, Jackob N, Anker, Lauren, Faerman, Afik, Brown, Randi E, Shamma, Ahmed, et al. Magnesium-ibogaine therapy in veterans with traumatic brain injuries. Nature Medicine 2024;30(2):373— 381 Dickinson, Jonathan E, Inzunza, Jose Adalberto Dominguez, Perez-Villa, Liliana, Millar, Trevor G, Pushparaj, Abhiram P. Case report: Ibogaine reduced severe neuropathic pain associated with a case of brachial plexus nerve root avulsion. Frontiers in Pain Research 2023 ;4(): 1256396 Koenig, Xaver, Hilber, Karl. The anti-addiction drug ibogaine and the heart: a delicate relation. Molecules 2015;20(2):2208— 2228 He, Dao-Yao, McGough, Nancy NH, Ravindranathan, Ajay, Jeanblanc, Jerome, Logrip, Marian L, Phamluong, Khanhky, et al. Glial cell line-derived neurotrophic factor mediates the desirable actions of the anti-addiction drug ibogaine against alcohol consumption. Journal of Neuroscience 2005;25(3):619— 628 Camicella, Sebastien, Kharazia, Viktor, Jeanblanc, Jerome, Janak, Patricia H, Ron, Dorit. GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proceedings ofthe National Academy of Sciences 2008;105(23):8114— 8119 Marton, Soledad, Gonzalez, Bruno, Rodriguez-Bottero, Sebastian, Miquel, Ernesto, Martinez-Palma, Laura, Pazos, Mariana, et al. Ibogaine administration modifies GDNF and BDNF expression in brain regions involved in mesocorticolimbic and nigral dopaminergic circuits. Frontiers in pharmacology 2019; 10(): 193Tang, Ben-qin, Li, Zi-wei, Li, Lin, Li, Bao-jing, Bian, Ya-qi, Yu, Guo-dong, et al. New iboga-type alkaloids from Ervatamia officinalis and their anti-inflammatory activity. Fitoterapia 2022;156():105085 Paskulin, Roman, Jamnik, Polona, Zivin, Marko, Raspor, Peter, Strukelj, Borut. Ibogaine affects brain energy metabolism. European journal of pharmacology 2006;552(l-3): 11-14 Paskulin, Roman, Jamnik, Polona, Danevcic, Tjasa, Kozelj, Gordana, Krstic- Milosevic, Dijana, Blagojevic, Dusko, et al. Metabolic plasticity and the energy economizing effect of ibogaine, the principal alkaloid of Tabemanthe iboga. Journal of Ethnopharmacology 2012; 143(1):319— 324 Govender, Demi, Moloko, Leila, Papathanasopoulos, Maria, Tumba, Nancy, Owen, Gavin, Calvey, Tanya. Ibogaine administration following repeated morphine administration upregulates myelination markers 2', 3'-cyclic nucleotide 3'- phosphodiesterase (CNP) and myelin basic protein (MBP) mRNA and protein expression in the internal capsule of Sprague Dawley rats. Frontiers in Neuroscience 2024;18(): 1378841 Dendrou, Calliope A, Fugger, Lars, Friese, Manuel A. Immunopathology of multiple sclerosis. Nature Reviews Immunology 2015;15(9):545-558 Thompson, Alan J, Banwell, Brenda L, Barkhof, Frederik, Carroll, William M, Coetzee, Timothy, Comi, Giancarlo, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. The Lancet Neurology 2018; 17(2): 162— 173 Fischl, Bruce. FreeSurfer. Neuroimage 2012;62(2):774— 781 Hodaie, M, Chen, DQ, Quan, J. Cortical thickness analysis in trigeminal neuralgia reflects unique changes related to treatment effect. Neuroimage 2009;47():S62 Calabrese, Massimo, Reynolds, Richard, Magliozzi, Roberta, Morra, Anna, Pitteri, Maddalena. Cortical pathology and cognitive impairment in multiple sclerosis. Expert Review of Neurotherapeutics 2020;20(8): 831-845Filippi, Massimo, Cercignani, M, Inglese, M, Horsfield, MA, Comi, Giancarlo. Diffusion tensor magnetic resonance imaging in multiple sclerosis. Neurology 2001;56(3):304— 311 Chen, David Q, DeSouza, Danielle D, Hayes, David J, Davis, Karen D, O’Connor, Paul, Hodaie, Mojgan. Diffusivity signatures characterize trigeminal neuralgia associated with multiple sclerosis. Multiple Sclerosis Journal 2016;22(l):51--63 Zhong, Jidan, Chen, David Qixiang, Nantes, Julia C, Holmes, Scott A, Hodaie, Mojgan, Koski, Lisa. Combined structural and functional patterns discriminating upper limb motor disability in multiple sclerosis using multivariate approaches. Brain imaging and behavior 2017;ll():754--768 Laule, Cornelia, Moore, GR Wayne. Myelin water imaging to detect demyelination and remyelination and its validation in pathology. Brain Pathology 2018;28(5):750— 764 Smith, Stephen M. Fast robust automated brain extraction. Human Brain Mapping 2002;17(3):143— 155 Gopinath, Karthik, Greve, Douglas N, Das, Sudeshna, Arnold, Steve, Magdamo, Cohn, Iglesias, Juan Eugenio. Cortical analysis of heterogeneous clinical brain MRI scans for large-scale neuroimaging studies. 2023 Billot, Benjamin, Greve, Douglas N, Puonti, Oula, Thielscher, Axel, Van Leemput, Koen, Fischl, Bruce, et al. SynthSeg: Segmentation of brain MRI scans of any contrast and resolution without retraining. Medical Image Analysis 2023;83(): 102789 Billot, Benjamin, Magdamo, Christine, Arnold, Steven E, Das, Sandhitsu, Iglesias, Juan Eugenio. Robust machine learning segmentation for large-scale analysis of heterogeneous clinical brain MRI datasets. Proceedings of the National Academy of Sciences 2023;120(9):e2216399120 Iglesias, Juan Eugenio, Billot, Benjamin, Balbastre, Yolanda, Magdamo, Christine, Arnold, Steven, Das, Sandhitsu, et al. SynthSR: a public Al tool to turn heterogeneousclinical brain scans into high-resolution Tl-weighted images for 3D morphometry.Science Advances 2023;9(5):eadd3607 Desikan, Rahul S, Segonne, Florent, Fischl, Bruce, Quinn, Brian T, Dickerson, Bradford C, Blacker, Deborah, et al. An automated labeling system for subdividing the human cerebral cortex on MRI scans into gyral based regions of interest. Neuroimage 2006;31(3):968--980 Fedorov, Andriy, Beichel, Reinhard, Kalpathy-Cramer, Jayashree, Finet, Julien, Fillion-Robin, Jean-Christophe, Pujol, Sonia, et al. 3D Slicer as an image computing platform for the Quantitative Imaging Network. Magnetic resonance imaging 2012;30(9):1323- 1341 Chen, David Qixiang, Quan, Jessica, Guha, Abhijit, Tymianski, Michael, Mikulis, David, Hodaie, Mojgan. Three-dimensional in vivo modeling of vestibular schwannomas and surrounding cranial nerves with diffusion imaging tractography. Neurosurgery 2011;68(4): 1077-1083 Avants, Brian B, Tustison, Nicholas J, Song, Gang, Cook, Philip A, Klein, Amo, Gee, James C. A reproducible evaluation of ANTs similarity metric performance in brain image registration. Neuroimage 2011;54(3):2033— 2044 Chen, David Q, Zhong, Jidan, Hayes, David J, Behan, Brendan, Walker, Matthew, Hung, Peter S-P, et al. Merged group tractography evaluation with selective automated group integrated tractography. Frontiers in neuroanatomy 2016;10():96 Chen, David Qixiang, Dell’Acqua, Flavio, Rokem, Ariel, Garyfallidis, Eleftherios, Hayes, David J, Zhong, Jidan, et al. Diffusion weighted image co-registration: investigation of best practices. BioRxiv 2019;(): 864108 Vidal-Pineiro, Didac, Parker, Nadine, Shin, Jean, French, Leon, Grydeland, Hakon, Jackowski, Andrea P, et al. Cellular correlates of cortical thinning throughout the lifespan. Scientific reports 2020;10(l):21803 Nevian, Thomas. The Cingulate Cortex: {{Divided}} in Pain. Nature Neuroscience 2017;20(ll): 1515— 1517Murray, PD, McGavem, DB, Sathomsumetee, S, Rodriguez, Moses. Spontaneous remyelination following extensive demyelination is associated with improved neurological function in a viral model of multiple sclerosis. Brain 2001;124(7):1403— 1416

Claims

What is claimed is:

1. A method for inducing lesion (preferably brain lesion) reduction in a patient in need thereof and / or Apparent Diffusion Coefficient (ADC) values (suggesting remyelination and reduced inflammation), comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

2. The method defined in Claim 1, wherein the treatment comprises an intial flood dose of ibogaine followed by a number of microdoses of ibogaine.

3. The method defined in Claim 2, wherein 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.

4. The method defined in Claim 2, wherein the initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 5 to about 21 mg / kg.

5. The method defined in Claim 2, wherein the 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 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 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 any one of Claims 2-7, wherein the initial flood dose of ibgaine does not exceed 1200 mg.

9. The method defined in any one of Claims 2-8, wherein the microdose of ibogaine is selected from a dosing range of from about 8 to about 300 mg.

10. The method defined in any one of Claims 2-8, wherein the microdose of ibogaine is selected from a dosing range of from about 10 to about 200 mg.

11. The method defined in any one of Claims 2-8, wherein the microdose of ibogaine is selected from a dosing range of from about 12 to about 150 mg.

12. The method defined in any one of Claims 2-8, wherein the microdose of ibogaine is selected from a dosing range of from about 15 to about 80 mg.

13. The method defined in any one of Claims 2-8, wherein the microdose of ibogaine is selected from a dosing range of from about 20 to about 60 mg.

14. The method defined in any one of Claims 2-13, wherein the micodose of ibogaine is administered daily.

15. The method defined in any one of Claims 2-14, wherein the microdose of ibogaine is administered for a duration of from about 1 to about 4 weeks.

16. The method defined in any one of Claims 2-14, wherein the microdose of ibogaine is administered for a duration of from about 2 to about 3 weeks.

17. A method for inducing neural structural changes (e.g., cortical and subcortical alterations, particularly in regions associated with pain and emotional processing) in a patient, comprising administering to the patient a therapeutically effective amount of ibogaine, ibogaine derivative, or a pharmaceutically acceptable salt and / or solvate thereof.

18. The method defined in Claim 17, wherein the treatment comprises an intial flood dose of ibogaine followed by a number of microdoses of ibogaine.

19. The method defined in Claim 18, wherein 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.

20. The method defined in Claim 18, wherein the initial flood dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 5 to about 21 mg / kg.

21. The method defined in Claim 18, wherein the 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.

22. The method defined in Claim 18, wherein the 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.

23. The method defined in Claim 18, wherein the 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.

24. The method defined in any one of Claims 18-23, wherein the initial flood dose of ibgaine does not exceed 1200 mg.

25. The method defined in any one of Claims 18-23, wherein the microdose of ibogaine is selected from a dosing range of from about 8 to about 300 mg.

26. The method defined in any one of Claims 18-23, wherein the microdose of ibogaine is selected from a dosing range of from about 10 to about 200 mg.

27. The method defined in any one of Claims 18-23, wherein the microdose of ibogaine is selected from a dosing range of from about 12 to about 150 mg.

28. The method defined in any one of Claims 18-23, wherein the microdose of ibogaine is selected from a dosing range of from about 15 to about 80 mg.

29. The method defined in any one of Claims 18-23, wherein the microdose of ibogaine is selected from a dosing range of from about 20 to about 60 mg.

30. The method defined in any one of Claims 18-29, wherein the micodose of ibogaine is administered daily.

31. The method defined in any one of Claims 18-30, wherein the microdose of ibogaine is administered for a duration of from about 1 to about 4 weeks.

32. The method defined in any one of Claims 18-30, wherein the microdose of ibogaine is administered for a duration of from about 2 to about 3 weeks.

33. The method defined in any one of Claims 18-32, wherein the patient is a mammal.

34. The method defined in any one of Claims 18-32, wherein the patient is a human.

Images