WO2025000092A1 - Ibogaine treatment - Google Patents

Abstract

There is disclosed a method of treatment of a patient undergoing ibogaine therapy, wherein the method comprises further administering a combination of: (a) a magnesium compound, (b) lactulose or an analog thereof, (c) sodium lactate or an analog thereof, and (d) dextrose or an analog thereof.

Description

IBOGAINE TREATMENT

CROSS-REFERENCE TO RELATED APPLICATION

[0001] The present application claims the benefit under 35 U.S.C. §119(e) of provisional patent application S.N. 63/523,774, filed June 28, 2024, the contents of which are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

FIELD OF THE INVENTION

[0002] In one of its aspects, the present invention relates to ibogaine treatment. More particularly, the present invention relates to ibogaine treament using a safety protocol that obviates or mitigates deleterious side effects associated with ibogaine treatment.

DESCRIPTION OF THE PRIOR ART

[0003] Ibogaine is a naturally occurring, psychoactive indole alkaloid derived from the root bark of the African shrub Tabernanthe iboga. In West Central Africa, low dosages of Tabernanthe iboga root bark have been employed by indigenous people against fatigue, hunger and thirst. Higher dosages are used for initiation rituals during religious ceremonies. Ibogaine ingestion can lead to intense visions with closed eyes reminding of a waking dream, often accompanied by a vivid recall of autobiographical visual memories (Alper, K.R.; Stajic, M.; Gill, J.R. Fatalities Temporally Associated with the Ingestion of Ibogaine. J. Forensic. Sci. 2012, 57, 398-412 (Alper et al.)).

[0004] The mechanisms by which ibogaine exerts its psychoactive effects in the brain are only poorly understood, which is attributable to the alkaloid’s complex pharmacology. Effects on multiple neurotransmitter systems via numerous brain targets have been reported. Among those, ibogaine interacts with neurotransmitter transporters, opioid receptors, sigma receptors, glutamate receptors, and nicotinic receptors in low micromolar concentrations (Alper, K.R. Ibogaine: A review. Alkaloids Chem. Biol. 2001, 56. 1-38 (Alper)). Long- lasting effects after ibogaine intake areattributed to the alkaloid’s long-lived active metabolite noribogaine (Baumann, M.H.; Pablo, J.P.; Ah, S.F.; Rothman, R.B.; Mash, D.C. Noribogaine (12-hydroxyibogamine): A biologically active metabolite of the antiaddictive drug ibogaine.

Ann. N. Y. Acad. Set. 2000, 914, 354-368).

[0005] Ibogaine’s medical history in the Western world began in the early 1900s when the substance was indicated for the treatment of asthenia and as a neuromuscular stimulant (Alper, ibid). In the 1940s and 1950s, ibogaine’s suitability as potential cardiovascular drug was studied (e.g., Schneider, J.A.; Rinehart, R.K. Analysis of the cardiovascular action of ibogaine hydrochi orid. Arch. Ini. Pharmacodyn. Ther. 1957, 110, 92-102). Later, following a discovery in in the 1960s, the drug received much attention because of its potential applicability as an anti-addiction medication. In animal studies, ibogaine has shown promising anti-addictive properties [Alper et al, ibid}.

[0006] Thus, ibogaine-treated rodents exhibit attenuated opioid withdrawal symptoms, and diminished self-administration of a variety of drugs of abuse including opioids, cocaine, nicotine, and alcohol (Glick, S.D.; Maisonneuve, I.S. Mechanisms of antiaddictive actions of ibogaine. Ann. N. Y. Acad. Sci. 1998, 844, 214-226). Anecdotal evidence suggests that ibogaine is also anti-addictive in humans. When ibogaine is administered to treat drug dependence, typically as single one-time dose (Alper, ibid), patients commonly report sustained resolution of the withdrawal syndromes within 12-18 h, and a reduction in drug craving for prolonged time periods up to several weeks (Brown, T.K. Ibogaine in the treatment of substance dependence. Curr. Drug Abuse Rev. 2013, 6, 3-16).

[0007] In 1993, the U.S. Food and Drug Administration (FDA) approved a clinical trial in humans to study the effects of ibogaine. The sudden death of a female patient, however, dampened further interest, and the National Institute on Drug Abuse (NIDA), critically advised by pharmaceutical industry consultants, opted not to fund additional human studies in 1995. Ibogaine was stigmatized as hallucinogen and stimulant with a possible abuse potential, and consequently classified as a Schedule 1 substance in the U.S. (Brown, ibid).

[0008] Mostly because of ibogaine’s status as a banned substance in the U.S., the development of the drug’s use in addiction treatment took then place outside conventional clinical and medical settings. The great and rapidly growing popularity of ibogaine as antiaddiction medication in alternative medicine prompted Frank Vocci, former director of NIDA’s anti-addiction drug development, to term ibogaine therapy “a vast, uncontrolled experiment” (Vastag, B. Addiction research. Ibogaine therapy: A “vast, uncontrolled experiment”. Science 2005, 308, 345-346).

[0009] Since that time the ibogaine “medical subculture” has continued to expand [Brown, ibid], and today, the alkaloid is used as an anti-addiction medication in alternative medicine in dozens of clinics worldwide [Apler et al., ibid; Brown, ibid],

[0010] Ibogaine’s complex pharmacology entails a considerable potential to generate adverse effects. Besides potential neurotoxic actions at dosages outside of the normal therapeutic range (e.g., Alper, ibid), ibogaine also affects the cardiovascular system, and, there are reports of mortality and morbidity that are temporally associated with the administration of the alkaloid (Xaver Koenig, X; Hilber, K. The Anti-Addiction Drug Ibogaine and the Heart: A Delicate Relation. Molecules 2015, 20, 2208-2228; Table 1). The first published report of fatalities temporally associated with ibogaine noted a total of 19 cases that occurred between 1998 and 2008 (Alper et al., ibid), 11 of which occurred prior to 2006. During a similar period, up until 2006, there were an estimated 3414 people who took ibogaine outside of Africa (Alper, K.R; Lotsof, H.S; Kaplan, C.D. The ibogaine medical subculture. Journal of Ethnopharmacology 2008, 115, 9-24). This suggests that under non-ideal circumstances, in individuals of potentially compromosied health because of drug use, the number needed to harm is 311 individuals.

[0011] It was hypothesised that the above-mentioned sudden deaths cases in humans were related to identifiable factors, including: cardiac arrhythmias, seizures resulting from benzodiazepine or alcohol withdrawal, her complications, and complications of other drugs or medications such as opioids. The cardiac arrythmias are most probably associated with ibogaine’s propensity to induce a QT interval prolongation in the electrocardiogram (ECG) [Alper et al., ibid], which is known to enhance the risk for life-threatening Torsade de pointes (TdP) arrhythmia generation (Sanguinetti, M.C.; Tristani-Firouzi, M. hERG potassium channels and cardiac arrhythmia. Nature 2006, 440, 463-469).

[0012] In response to these identifiable risks, a safety protocol was published in 2015 that provides instructions on intake, screening, drug interactions, monitoring, pre-treatment and post-treatment care in order to methodologically mitigate the risks described above (Dickinson, J.; McAlpin, J.; Wilkins, C; Fitzsimmons, C; Guion, P; Paterson, T; Green, D; Chaves, B.R. Clinical Guidelines for Ibogaine Assisted Detoxification. Global Ibogaine Therapy Alliance 2015. Retrieved from https://www.ibogaineguidelines.com).

[0013] Magnesium sulfate, administered through intravenous injections, is a known treatment Toursades de points due to its ability to mitigate QT interval prolongation (https://www.ahaioumals.Org/doi/10.1161/01.CIR.77.2.392). One of the pre-treatment recommendations listed in GITA’s Clinical Guidelines is the use of “1 liter of lactated ringer or normal saline, along with 1 ampule of magnesium sulphate” as a prophylaxis to prevent QT interval prolongation.

[0014] To date, ibogaine research has focused predominantly on its potential as a treatment for substance use disorders (SUDs) (Brown, T. K. & Alper, K. Treatment of opioid use disorder with ibogaine: detoxification and drug use outcomes. Am. J. Drug Alcohol Abuse 44, 24-36 (2018)). Some studies of ibogaine for SUDs also have noted improvements in selfreported measures of mood (Noller, G. E., Frampton, C. M. & Yazar-Klosinski, B. Ibogaine treatment outcomes for opioid dependence from a twelve-month follow-up observational study. Am. J. Drug Alcohol Abuse 44, 37-46 (2018)).

[0015] However, no studies have prospectively validated effects on mood with more rigorous clinician-rated instruments. US Special Operations Forces (SOF) Veterans (SOV) have noted subjective improvements following ibogaine (Armstrong, S. B. et al. Prospective associations of psychedelic treatment for co-occurring alcohol misuse and posttraumatic stress symptoms among United States Special Operations Forces Veterans. Mil. Psychol. 1-8 (2023) doi: 10.1080/08995605.2022.2156200).

[0016] SOF are deployed at a greater pace and to higher intensity combat than conventional military, exposing them to greater allostatic load and risk of injury, including from blast exposure (Garcia, A. et al. Neurobehavioral Symptoms in U.S. Special Operations Forces in Rehabilitation After Traumatic Brain Injury: A TBI Model Systems Study. Mil. Med. 187, 1412-1421 (2022)). This, in turn, has been proposed to result in a unique pattern of physical, cognitive, behavioral, psychiatric, and endocrine-related problems that negatively impact ongoing functioning across several domains (Frueh, B. C. et al. “Operator syndrome”: A unique constellation of medical and behavioral health-care needs of military special operation forces. Int. J. Psychiatry Med. 55, 281-295 (2020)). [0017] While studies reporting specifically on SOV treatment outcomes are lacking (Garcia, A. et al. Health Conditions Among Special Operations Forces Versus Conventional Military Service Members: A VA TBI Model Systems Study. J. Head Trauma Rehabil. 37, E292- E298 (2022)), individuals with combat-related TBI and comorbid conditions including PTSD and depression may have higher suicide risk (McIntire, K. L. et al. Factors Increasing Risk of Suicide after Traumatic Brain Injury: A State-of-the-Science Review of Military and Civilian Studies. Brain Inj. 35, 151-163 (2021)).

[0018] Given this substantial burden of ongoing disability and suicide risk in SOV, additional treatment options are needed for using ibogaine.

[0019] More particularly, there is an unmet need for a safety protocol that obviates or mitigates deleterious side effects associated with ibogaine treatment.

SUMMARY OF THE INVENTION

[0020] It is an object of the present invention to obviate or mitigate at least one of the above- mentioned disadvantages of the prior art.

[0021] It is another object of the present invention to provide a novel safety protocol that obviates or mitigates deleterious side effects associated with ibogaine treatment.

[0022] It is another object of the present invention to provide a novel treatment using ibogaine that obviates or mitigates deleterious side effects associated with ibogaine treatment.

[0023] Accordingly, in one of its aspects, the present invention provides a method of treatment of a patient undergoing ibogaine therapy, wherein the method comprises further administering a combination of: (a) a magnesium compound, (b) lactulose or an analog thereof, (c) sodium lactate or an analog thereof, and (d) dextrose or an analog thereof.

[0024] Thus, the present inventor has discovered that combining ibogaine treatment with a specific combination of other ingredients suprising obviates or mitigates deleterious side effects associated with ibogaine (alone) treatment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS [0025] Various terms used throughout this specification are intended to have the following meanings.

[0026] 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.

[0027] 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.

[0028] 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.

[0029] 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.

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 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

[0034] The present invention provides methods of treating 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, ibogaine analogs, or extractions and purifications of alkaloids found in Tabernanthe ibogd) 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 multiple sclerosis disease, traumatic brain injury, some neuropathic pain conditions, other neurodegenerative disorders, mental health disorders, substance use disorders or symptoms of any of these. The method includes the step of administering to the mammal a therapeutic amount of an amount of ibogaine, an ibogaine analog, or extractions and purifications of alkaloids found in Tabernanthe iboga, alone or together, sufficient to treat the disease or disorder or symptom thereof, under conditions such that the disease or disorder is treated.

[0035] 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.

[0036] 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). [0037] 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.

[0038] 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).

[0039] 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, traumatic brain injury, substance use disorder or behavioural addiction, etc. 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.

[0040] 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 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.

[0041] The invention further relates to methods for treatment and/or prevention of multiple sclerosis, traumatic brain injury, some neuropathic pain conditions, other neurodegenerative disorders, mental health disorders, substance use or behavior disorders 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.

[0042] 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, traumatic brain injury, neuropathic pain conditions, other neurodegenerative disorders, mental health disorders, substance use or behavioral disorders, and/or other disease/disorders affecting the central nervous system, including mice, rats, rabbits, nonhuman primates, such as monkeys, are also within the scope of the invention (e.g. experimental allergic encephalomyelitis (EAE)).

[0043] 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).

[0044] 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 axons and 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.

[0045] 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.

[0046] 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.

[0047] 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.

[0048] 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.

[0049] Subjects exhibiting these symptoms are within the scope of the present invention.

[0050] 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 with incomplete 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

[0051] Ibogaine has been used as a botanical preparation from the root bark of Tabernathe iboga for over 100 years in various forms, including as a crude preparation, as a total alkaloid extract, as a purified total alkaloid extract, as a complete botanical drug, and as isolated ibogaine, which was marketed in France until about 1970. More recently, semi-synthetic ibogaine has been produced from voacangine or other similar alkaloids (Dickinson, J. Iboga Root: Dynamics of Iboga’s African Origins and Modem Medical Use. Journal of the American Botanical Council 2016, 109, 48-57,). Synthetic ibogaine and iboga analogs can be produced by various means. 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.

[0052] 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., 13 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.

[0053] "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 Tabernanth iboga, a shrub endemic to Central Africa, particularly Gabon (Dickinson, ibid). In some cases, ibogaine mixtures contain the other alkaloids found in Tabernanthe iboga, such as ibogamine, ibogaline, tabemanthine, coronoradine, voacangine, etc. Ibogaine, these other alkaloids, and iboga analogs can also be semi-synthesized or 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 Taberntanthe iboga, or other alkaloids found present in it, including ibogamine, ibogaline, tabemanthine, coronoradine, voacangine, etc.

Treatment Methods

[0054] In a preferred embodiment, the dose of ibogaine is selected from a dosing range (adjusted by patient body weight) of from about 2 to about 50 mg/kg, from about 3 to about 40 mg/kg, preferably from about 4 to about 30 mg/kg, preferably from about 5 to about 28 mg/kg, preferably from about 6 to about 24 mg/kg.

[0055] In some cases, one or more booster dosages of 50-600 mg (typically 100-500 mg) can be provided 12 hours or more before or after initial dosage 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.

[0056] 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 ibogaine, and its metabolite noribogaine.

Dosing Instructions [0057] Ibogaine dosages are calculated by weight, and in a preferred embodiment dosages over 6 mg/kg are divided into several dosages, between 2-5 dosages, which are administered within a 30-to-240-minute window in order to evaluate onset of effects and make adjustments for a desired therapeutic effect.

[0058] The present invention relates to combining ibogaine treatment with a specific combination of other ingredients to suprisingly obviate or mitigate deleterious side effects associated with ibogaine (alone) treatment. More specifically, present invention relates to combining ibogaine treatment with a combination of the following components: (i) lacutulose or an analog thereof; (ii) magnesium or an analog thereof; and (iii) dextrose or an analog thereof.

Lactulose and Analogs

[0059] Lactulose is an osmotic laxative used mainly to treat constipation and, in higher doses, hepatic encephalopathy. Generally, as a sugar, it is not metabolized in the body, so it reaches the colon intact, where it attracts water and promotes bowel movement.

[0060] It is known as a disaccharide used to treat constipation and help reduce the amount of ammonia in the blood of people with liver disease. It works by drawing water into the colon, which helps to soften the stool and stimulate bowel movements. In the case of liver disease, it works by trapping ammonia in the colon, where it is excreted.

[0061] Lactulose is commercially available under the following brand names Enulose™, Generlac™, Constulose™ and Kristalose™. The preferred dose is from about 5 g to about 40 gram per day, preferably from about 7 g to about 30 g per day, preferably from about 10 to about 20 g per day. For children (e.g., less than 16 years of age), the dose depends on the age of the child and will usually be lower than the adult dose. In preferred cases, if the patient does not excrete for 8 hours following an initial dose of lactulose, an additional dosage can be administered after at least 6 or 8 hours.

[0062] There are analogs of lactulose with similar effects that can be used for similar purposes.

[0063] For example: [0064] Polyethylene glycol (MiraLAX, Glycolax): this is a type of laxative that works by drawing water into the colon, similar to lactulose. It is often used to treat occasional constipation. The preferred dose is from about 10 g to about 25 g, preferably from about 12 g to about 20g, preferably from about 15 g to about 20 g, preferably 17 g. It is preferred to administer the compound as an oral dosage form.

[0065] Lactitol (Pizensy): This is a sugar alcohol used to treat chronic idiopathic constipation in adults. The preferred dose is from about 0.2 g/kg/day to about 1.0 g/kg/day, preferably from about 0.3 g/kg/day to about 0.8 g/kg/day, preferably from about 0.5 g/kg/day to about 0.7 g/kg/day. It is preferred to administer the compound as an oral dosage form.

[0066] Other treatments to reduce ammonia: In cases of hepatic encephalopathy (a complication of liver disease), other treatments may be used to help reduce ammonia levels. One example is rifaximin, an antibiotic that acts in the intestine to reduce ammonia production.

[0067] Other medications with similar effects include other osmotic laxatives such as:

[0068] Magnesium hydroxide (Milk of Magnesia™). The preferred dose is from about 10 mL to about 80 mL per day, preferably from about 20 mL to about 70 mL per day, preferably from about 30 mL to about 60 mL per day. It is preferred to administer the doses in divided amounts.

[0069] Sorbitol. The preferred dose is from about 10 mL to about 200 mL per day as a 70% solution, preferably from about 20 mL to about 180 mL per day as a 70% solution, preferably from about 30 mL to about 150 mL per day as a 70% solution.

[0070] Glycerin suppositories. The preferred dose is one suppository inserted into the rectum.

[0071] Oral stool softeners (Colace™, Surfak™)

[0072] Colace™: The preferred dose is from abou 100 mg to about 500 mg administered orally.

[0073] Surfak™: The preferred dose is 320 mg to 500 mg administered orally.

[0074] Oral stimulants (Dulcolax™) [0075] Dulcolax™: The preferred dose is from about 5 mg to about 10 mg.

Magnesium and Analogs

[0076] While not wishing to be bound by any particular theory or mode of action, it is believed that magnesium intake is associated with a lower risk of hypertension and heart disease. It is believed it can help regulate heart rhythm and is often given to people who have suffered a heart attack to reduce the risk of arrhythmia (irregular heartbeat).

[0077] Magnesium can be administered intravenously (IV) in a healthcare setting for a variety of reasons, such as severe magnesium deficiency, eclampsia and pre-eclampsia during pregnancy, acute asthma attack, arrhythmia or migraine.

[0078] The following non-limiting types of magnesium preparations are preferably administered intravenously.

[0079] Magnesium sulfate: This is the most commonly used form of intravenous magnesium. It is used for electrolyte balance, as prophylaxis to ibogaine-assisted treatment and certain cardiac arrhythmias. The preferred dose is from about 0.2 g to about 3.0 g, preferably from about 0.5 g to about 2 g, preferably 1 g.

[0080] The following is a list of different types of magnesium (including liposomal formulations).

[0081] Magnesium Glycinate: Known to be easily absorbed and gentle on the stomach, magnesium glycinate is commonly used to correct magnesium deficiencies and may also help reduce symptoms of depression, anxiety and insomnia. The preferred daily dose is from about 100 mg to about 1000 mg, preferably from about 200 mg to about 700 mg, preferably from about 300 mg to about 500 mg. It is preferred to administer the compound as an oral dosage form.

[0082] Magnesium L-threonate: This form of magnesium is believed to be effective in crossing the blood-brain barrier and therefore may benefit cognitive functions. The preferred daily dose is from about 0.5 g to about 3.0, preferably from about 0.7 g to about 2.5 g, preferably from about 1.0 g to about 2.0 g. It is preferred to administer the compound as an oral dosage form. [0083] Magnesium malate: This form of magnesium is commonly used in people suffering from fatigue or fibromyalgia, as malate is a substrate in the cellular energy cycle. The preferred daily dose is from about 100 mg to about 1000 mg, preferably from about 150 mg to about 700 mg, preferably from about 200 mg to about 500 mg. It is preferred to administer the compound as an oral dosage form.

[0084] Magnesium taurate: This form combines magnesium and the amino acid taurine to potentially contribute to cardiovascular health. The preferred daily dose is from about 50 mg to about 1000 mg, preferably from about 75 mg to about 700 mg, preferably from about 100 mg to about 500 mg. It is preferred to administer the compound as an oral dosage form.

Dextrose and Analogs

[0085] Dextrose, also known as glucose, is a simple form of sugar that the body uses for energy.

[0086] Intravenous dextrose is a common way to deliver glucose directly into the bloodstream to treat and prevent hypoglycemia, or low blood sugar levels, especially in a hospital setting.

[0087] In the context of the present invention, dextrose may be administered via a number of non-limiting routes/modes of administration, for example:

[0088] D5W (5% dextrose in water), consisting of 278 mmol/L dextrose;

[0089] D5NS (5% dextrose in normal saline), which also contains normal saline (0.9% w/v NaCl);

[0090] D5LR (5% dextrose in Ringer's Lactate solution); and/or

[0091] D50 50% dextrose in water.

[0092] The preferred dose is from about 0.1 g to about 3.0, preferably from about 0.3 g to about 2.5 g, preferably from about 0.5 g to about 2.0 g. Preferably, the dose is administered intravenously.

Thiamine Hydrochloride and Analogs [0093] In a preferred embodiment, the safety protocol further comprises administration of thiamine hydrochloride and analogs thereof.

[0094] In a preferred embodiment, a prodrug of thiamine is use. Preferably, the prodrug is benfotiamine which is a synthetic S-acyl derivative of thiamine. It is converted to thiamine in the body and is better absorbed than normal thiamine, making it potentially useful in the treatment of certain medical conditions such as diabetic neuropathy. The preferred dose is from about 10 mg to about 500 mg, preferably from about 25 mg to about 350 mg, preferably from about 50 mg to about 200 mg. Preferably, the dose is administered intravenously.

[0095] In a preferred embodiment, a synthetic derivative of thiamin is used.

[0096] In one preferred embodiment, the synthetic derivative is sulbutiamine which is a synthetic derivative of thiamine capable of more easily crossing the blood-brain barrier. This gives it potential as a treatment for fatigue and certain neurodegenerative conditions. The preferred dose is from about 100 mg to about 1000 mg, preferably from about 200 mg to about 600 mg, preferably from about 300 mg to about 500 mg, preferably 400 mg. It is preferred to administer the compound as an oral dosage form.

[0097] In another preferred embodiment, the synthetic derivative is fursultiamine (thiamine tetrahydrofurfuryl disulfide) which has been used in the treatment of chronic fatigue and other conditions. The preferred dose is from about 100 mg to about 1000 mg, preferably from about 200 mg to about 600 mg, preferably from about 300 mg to about 500 mg, preferably 400 mg. Preferably, the dose is administered intravenously.

[0098] In a preferred embodiment, a natural derivative of thiamin is used. Preferably, the natural derivative is allithiamine which is a natural derivative of thiamine found in garlic and onions. It is also better absorbed than regular thiamine. The preferred dose is from about 10 mg to about 500 mg, preferably from about 25 mg to about 350 mg, preferably from about 50 mg to about 200 mg. Preferably, the dose is administered intravenously.

Riboflavin and Analogs

[0099] In a preferred embodiment, the safety protocol further comprises administration of riboflavin and analogs thereof. [0100] Riboflavin, also known as vitamin B2, plays a crucial role in energy production, cell function, growth and development. It is also important for the metabolism of fats, drugs and steroids.

[0101] Preferably, riboflavin is administered in the form of riboflavin 5'phosphate sodium. The preferred dose is from about 2 mg/mL to about 100 mg/mL. Preferably, the dose is administered intravenously or intramuscularly.

Nicotinamide and Analogs

[0102] In a preferred embodiment, the safety protocol further comprises administration of nicotinamide and analogs thereof.

[0103] In one preferred embodiment, nicotinamide is used in the form of nicotinamide riboside. Nicotinamide riboside is precursor of nicotinamide adenine dinucleotide (NAD+), a crucial coenzyme involved in many metabolic and cellular processes. Nicotinamide riboside is being studied for its potential to increase NAD+ levels and thus improve a number of health outcomes related to aging, brain health, heart health, etc. The preferred dose is from about 500 mg to about 3000 mg, preferably from about 750 mg to about 2500 mg, preferably from about 1000 mg to about 2000 mg. Preferably, the dose is administered intravenously.

[0104] In another preferred embodiment, nicotinamide is used in the form of nicotinamide mononucleotide. Nicotinamide mononucleotide is another precursor of NAD+. Nicotinamide mononucleotide is used by cells to produce NAD+, and its potential to delay aging, improve energy metabolism and promote brain health is being investigated.

Pyridoxal and Analogs

[0105] In a preferred embodiment, the safety protocol further comprises administration of pyridoxal and analogs thereof.

[0106] In one preferred embodiment, pyridoxal is used in the form of pyridoxamine which is another natural form of vitamin B6. It is converted to pyridoxal 5'-phosphate in the body. [0107] In another preferred embodiment, pyridoxal is used in the form of pyridoxal 5'- phosphate which is the biologically active form of vitamin B6. It acts as a coenzyme in a wide range of enzymatic reactions, particularly those involving amino acid metabolism.

[0108] In another preferred embodiment, pyridoxal is used in the form of pyridoxine 5'- phosphate. Pyridoxine 5'-phosphate is another phosphorylated form of vitamin B6, but is not as biologically active as pyridoxal 5'-phosphate.

[0109] In another preferred embodiment, pyridoxal is used in the form of pyridoxal hydrochloride. This is a form of pyridoxine that is often used in vitamin B6 supplements.

[0110] In another preferred embodiment, pyridoxal is used in the form of 4-deoxypyridoxine and 4'-deoxypyridoxine. These are synthetic vitamin B6 antagonists that are often used in research to induce vitamin B6 deficiency in laboratory animals.

[0111] In another preferred embodiment, pyridoxal is used in the form of cycloserine which is a drug used to treat tuberculosis that acts as a structural analog of pyridoxal. It inhibits enzymes that require pyridoxal 5'-phosphate as a coenzyme.

[0112] The preferred dose is from about 2 g to about 10 g, preferably from about 3 g to about 8 g, preferably from about 4 g to about 6 g, preferably 5 g. Preferably, the dose is administered intravenously.

[0113] Preferred embodiments of the present invention will be described with reference to the follow Example which should not be used to construe or limit the scope of the invention.

Background data

[0114] The present inventor and his team have treated and documented over 1005 individuals with ibogaine, together with magnesium sulfate and the safety protocol ingredients described in Paragraph [0120] below. During this treatement, no reported fatalities occurred, and no instances of symptomatic cardiac arrythmia were reported. Five instances of cardiac intervention had to be performed, including two instances of asymptomatic ventricular tachycardia successfully treated with lidocaine, and three instances of asymptomatic bradycardia successfully treated with atropine. During this period, based on number needed to harm from the prior art (311), three or more fatalities would have been expected if the present safety protocol described had not been administered.

Pre-post Study Evaluating the Safety and Efficacy of Ibogaine-Magnesium Therapy in Veterans with Sequelae of Repeated Blast Exposure

[0115] Study participants were 30 male SOV who had independently scheduled themselves for treatment in Mexico after being approved for a grant by a non-profit organization, Veterans Exploring Treatment Solutions (VETS). The Applicant conducted its own application process and medical screening, including routine blood work, electrocardiogram, and instruction to discontinue certain medications with potentially concerning drug-drug interactions.

[0116] Potential participants then were screened for eligibility in a research study by a research team at Stanford University (see the following website link for addition details: https://www.dini caltrials. gov/ study /NCT04313712?intr=ibogaine%20with%20magnesium% 20treatment&rank=l). Participants were eligible if they were veterans between 18 and 70 years of age; were able to provide informed consent; had a history of head trauma, combat, or blast exposure; and had no contraindication to MRI. Exclusion criteria included history of a neurological disorder (excluding sequelae of TBI); history of any psychotic symptoms or disorders; being at risk for suicidal behavior during the study in the judgement of the investigator; having a significant clinical abnormality on screening physical exam that could affect safety or study integrity; recent or concurrent participation in another study with a drug or device; history of cardiovascular, liver, or kidney problems; pregnancy; or, any other condition that would affect the individual’s ability to safely participate.

[0117] Racial/ethnic identity was determined by the participants using classification terms provided by the researchers. Classification terms were: American Indian or Alaska Native; Asian; Black or African American; Native Hawaiian or Other Pacific Islander; White; Hispanic or Latino (ethnicity); Not Hispanic or Latino (ethnicity).

[0118] Gender was determined by the participants using classification terms provided by the researchers. Classification terms were: "male", "female", or "other".

Procedure [0119] Upon arrival at the clinic, participants were assessed by the clinic’s medical staff including bloodwork, electrocardiogram, and urinalysis. Group preparatory and ceremonial activities took place. Day 2 involved additional group preparatory activities and an 8-hour fast prior to the treatment, which began on the evening of Day 2 and continued through Day 3. Integration activities occurred on Day 4, and participants returned to the United States on the evening of Day 5.

[0120] With subjects in the fasting state as noted above, clinic personnel administered an intravenous infusion of 1 g of magnesium sulfate and an oral gastrointestinal protective agent 1-2 hrs prior to treatment. The oral ibogaine dosing protocol consisted of an initial test dose of 2-3 mg/kg of semi-synthetic, ethically sourced ibogaine hydrochloride (98+% pure). Depending on response, after ~40 mins additional doses of ibogaine up to a total of <14 mg/kg were administered within a total 2-hour period. Approximately 12 hours after administration of ibogaine, participants were administered the following:

• Lactulose 50mg oral

• Sol Hartman 1000 Ml IV

• Magnesium sulfate 1g IV

• Dextrose 5.0g IV

• Thiamine Hydrochloride 10 mg IV

• Riboflavin 4. Omg IV

• Nicotinamide 50 mg IV

• Pyridoxine 5g IV

[0121] Medical staff (MD, RN, or EMT) were onsite at a ratio of at least 1 staff per 2 patients throughout treatment for monitoring and management, but no specific coaching or psychological support was provided during treatment. For 12-16 hours following ibogaine administration, blood pressure and pulse oximetry were monitored three times a day, and QTc was monitored via continuous 5-lead ECG. In one participant’s case, a 4 mg/kg booster dose was provided 12 hours after the initial dose given insufficient treatment intensity/duration as judged by clinic personnel; medical monitoring was extended accordingly.

Treatment Experience

[0122] Alper (ibid) describes therapeutic dosing of ibogaine typically leading to three sequential stages beginning approximately one to three hours post-ingestion: “acute” (-4- 8hrs), “evaluative” (~8-20hrs), and “residual” (~24-72hrs). Dreamlike states of consciousness begin during the acute stage, usually with closed eyes. Participants were able to visually orient themselves in the room as needed during their experiences. This acute stage leads into contemplation of the experiences from the previous stage. The residual stage involves reintegration with the environment as any lingering effects resolve.

[0123] 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.

[0124] 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.

Claims

What is claimed is:

1. A method of treatment of a patient undergoing ibogaine therapy, wherein the method comprises further administering a combination of: (a) a magnesium compound, (b) lactulose or an analog thereof, (c) sodium lactate or an analog thereof, and (d) dextrose or an analog thereof.

2. The method defined in Claim 1, wherein component (a) comprises magnesium sulfate.

3. The method defined in Claim 2, wherein component (a) is administered in a dose of from about 0.2 g to about 3.0 g.

4. The method defined in Claim 2, wherein component (a) is administered in a dose of from from about 0.5 g to about 2 g.

5. The method defined in Claim 2, wherein component (a) is administered in a dose of about 1 g.

6. The method defined in any one of Claims 2-5, wherein component (a) is administered intravenously.

7. The method defined in Claim 1, wherein component (a) comprises magnesium glycinate.

8. The method defined in Claim 7, wherein component (a) is administered in a dose of from about 100 mg to about 1000 mg.

9. The method defined in Claim 7, wherein component (a) is administered in a dose of from about 200 mg to about 700 mg.

10. The method defined in Claim 7, wherein component (a) is administered in a dose of from about 300 mg to about 500 mg.

11. The method defined in any one of Claims 7-10, wherein component (a) is administered orally.

12. The method defined in Claim 1, wherein component (a) comprises magnesium L- threonate.

13. The method defined in Claim 12, wherein component (a) is administered in a dose of from about 0.5 g to about 3.0.

14. The method defined in Claim 12, wherein component (a) is administered in a dose of from about 0.7 g to about 2.5 g.

15. The method defined in Claim 12, wherein component (a) is administered in a dose of from about 1.0 g to about 2.0 g.

16. The method defined in any one of Claims 12-15, wherein component (a) is administered orally.

17. The method defined in Claim 1, wherein component (a) comprises magnesium malate.

18. The method defined in Claim 17, wherein component (a) is administered in a dose of from about 100 mg to about 1000 mg.

19. The method defined in Claim 17, wherein component (a) is administered in a dose of from about 150 mg to about 700 mg.

20. The method defined in Claim 17, wherein component (a) is administered in a dose of from about 200 mg to about 500 mg.

21. The method defined in any one of Claims 17-20, wherein component (a) is administered orally.

22. The method defined in Claim 1, wherein component (a) comprises magnesium taurate.

23. The method defined in Claim 22, wherein component (a) is administered in a dose of from about 50 mg to about 1000 mg.

24. The method defined in Claim 22, wherein component (a) is administered in a dose of from about 75 mg to about 700 mg.

25. The method defined in Claim 22, wherein component (a) is administered in a dose of from about 100 mg to about 500 mg.

26. The method defined in any one of Claims 22-25, wherein component (a) is administered orally.

27. The method defined in any one of Claims 1-26, wherein component (b) comprises lactulose.

28. The method defined in Claim 27, where component (b) is administered in a dose of from about 5 g to about 40 gram per day, preferably from about 7 g to about 30 g per day, preferably from about 10 to about 20 g per day.

29. The method defined in any one of Claims 1-26, wherein component (b) comprises polyethylene glycol.

30. The method defined in Claim 29, where component (b) is administered in a dose of from about 10 g to about 25 g, preferably from about 12 g to about 20g, preferably from about 15 g to about 20 g, preferably 17 g.

31. The method defined in any one of Claims 1-26, wherein component (b) comprises lactitol.

32. The method defined in Claim 31, where component (b) is administered in a dose of from about 0.2 g/kg/day to about 1.0 g/kg/day, preferably from about 0.3 g/kg/day to about 0.8 g/kg/day, preferably from about 0.5 g/kg/day to about 0.7 g/kg/day.

33. The method defined in any one of Claims 1-26, wherein component (b) comprises magnesium hydroxide.

34. The method defined in Claim 33, where component (b) is administered in a dose of from about 10 mL to about 80 mL per day, preferably from about 20 mL to about 70 mL per day, preferably from about 30 mL to about 60 mL per day.

35. The method defined in any one of Claims 1-26, wherein component (b) comprises sorbitol.

36. The method defined in Claim 35, where component (b) is administered in a dose of from about 10 mL to about 200 mL per day as a 70% solution, preferably from about 20 mL to about 180 mL per day as a 70% solution, preferably from about 30 mL to about 150 mL per day as a 70% solution.

37. The method defined in any one of Claims 27-36, wherein component (b) is administered orally.

38. The method defined in any one of Claims 1-37, wherein component (c) comprises Sol

Harman solution.

39. The method defined in Claim 38, wherein component (c) is administered intravenously.

40. The method defined in any one of Claims 1-39, wherein the combination further comprises: thiamine hydrochloride or an analog thereof.

41. The method defined in any one of Claims 1-40, wherein the combination further comprises: riboflavin or an analog thereof.

42. The method defined in any one of Claims 1-41, wherein the combination further comprises: nictinamide or an analog thereof.

43. The method defined in any one of Claims 1-42, wherein the combination further comprises pyridoxal or an analog thereof.

44. The method defined in any one of Claims 1-43, where the patient is undergoing ibogaine therapy for treatment of PT.

45. The method defined in any one of Claims 1-43, where the patient is undergoing ibogaine therapy for treatment of addiction.

46. The method defined in any one of Claims 1-43, where the patient is undergoing ibogaine therapy for treatment of multiple sclerosis.

47. The method defined in any one of Claims 1-43, where the patient is undergoing ibogaine therapy combat-related traumatic brain injury (TBI).

48. The method defined in any one of Claims 1-43, where the patient is undergoing ibogaine therapy for a comorbid condition.

49. The method defined in any one of Claims 1-43, where the patient is undergoing ibogaine therapy for including post-traumatic stress disorder (PTSD).

50. The method defined in any one of Claims 1-43, where the patient is undergoing ibogaine therapy for depression.