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IBOGAINE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Ibogaine, an indole alkaloid, is obtained from the root of the West African shrub, Tabernanthe iboga (Apocynaceae).

Specific Substances

    1) NIH-10567
    2) Eboka
    3) IBO
    4) Iboga
    5) Ibogaine hydrochloride
    6) Ibogamine, 12-methoxy-monohydrochloride
    7) Ibogaine, monohydrochloride
    8) Molecular Formula: C20-H26-N2-O
    9) CAS 5934-55-4

Available Forms Sources

    A) FORMS
    1) In France, ibogaine (8 mg tablets) was marketed from 1939 to 1970, under the trade name Lambarene. As a neuromuscular stimulant, it was recommended to be used for fatigue, depression, and recovery from infectious diseases (Alper, 2001; Mash DC; Kovera CA; Buck BE, 1998).
    2) In the West, ibogaine hydrochloride is usually administered as a fine off-white powder, either synthesized or chemically extracted from the root of iboga plant (N Sandberg , 2001).
    3) In 1991, the US National Institute for Drug Abuse, (NIDA), began studying ibogaine to evaluate its safety and creating treatment protocols. In 1993, the US Food and Drug Administration (FDA) approved clinical trials with ibogaine (dosage levels of 1, 2, and 5 mg/kg). Single administration of fixed dosages of ibogaine 150 and 300 mg vs placebo for the indication of cocaine dependence was also studied. The death of a young heroin dependent woman during treatment in Holland as well as contractural and funding problems have stopped the clinical trials (Alper, 2001).
    B) USES
    1) In recent years, ibogaine has been used to treat both drug (eg, heroin, methadone, cocaine) and alcohol dependency. It has been suggested that a single administration of ibogaine has the ability to either prevent or ameliorate the symptoms of drug withdrawal and reduce drug craving (usually within 1 to 2 hours) (N Sandberg , 2001; Alper, 2001).
    2) In traditional medicine, the yellow-colored root is used as a hallucinogen (Anon, 1994; Duke, 1985). In West Africa, iboga plant is used as a medicinal and ceremonial agent (Alper et al, 2000).
    a) In its native growing regions, iboga plant has been used as an important force against the spread of Christianity and Islam. In addition, after consuming the plant, indigenous people believe that they can retrieve hidden treasures buried by individuals subjected to the intoxicant during their former lives. Failure to retrieve these hidden treasures may result in "sudden and mysterious deaths" among villagers (Anon, 1994).
    b) In Central Africa (Gabon, Zaire, Cameroon), the Bwiti religious members use iboga in initiation ritual/rebirth ceremony to assist in the transition from adolescence into adulthood (Lotsof & Alexander, 2001; N Sandberg , 2001; Jellin et al, 2000).
    c) In addition, it is used in low doses to combat fatigue, hunger and thirst, and in high doses for its psychoactive properties as a sacrament in religious rituals (Cienki et al, 2001; Mash DC; Kovera CA; Buck BE, 1998).
    d) OTHER REPORTED USES: Used as an aperitif, aphrodisiac, CMS-stimulant, tonic, hallucinogenic, for convalescence, debility, fever, hypertension, and neurasthenia (Jellin et al, 2000; Anon, 1994; Duke, 1985).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Ibogaine has been used to treat both drug (eg, heroin, methadone, cocaine) and alcohol dependency. It has been suggested that a single administration of ibogaine has the ability to either prevent or ameliorate the symptoms of drug withdrawal and reduce drug craving (usually within 1 to 2 hours). It is also used as an aperitif, aphrodisiac, CMS-stimulant, tonic, hallucinogenic, for convalescence, debility, fever, hypertension, and neurasthenia. In Central Africa (Gabon, Zaire, Cameroon), the Bwiti religious members use iboga in initiation ritual/rebirth ceremony to assist in the transition from adolescence into adulthood. In the United States, ibogaine is classified as a Schedule I drug.
    B) PHARMACOLOGY: Ibogaine, a hallucinogenic indole alkaloid, is extracted from the root of the West African shrub, Tabernanthe iboga (Apocynaceae). It inhibits cholinesterase, leading to the accumulation of synaptic acetylcholine.
    C) TOXICOLOGY: Cholinergic hyperactivity can cause slowing of the heart rate, hypotension, seizures, paralysis, and respiratory arrest. The pharmacologic effects (CNS stimulation, mild excitation, euphoria, visual and auditory hallucinations) are usually dose-dependent. The indole alkaloids, ibogaine, ibogamone, iboluteine, and tabernanthine are responsible for the hallucinogenic properties of ibogaine. Hallucinations accompanied by anxiety and apprehension are usually only experienced at the highest doses. Ibogaine can prolong QT interval, as it has central 5HT-2A agonist activity.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Ibogaine is generally well tolerated. Nausea, vomiting, ataxia, and mild tremor are the most frequent side effects reported.
    2) SEVERE TOXICITY: Bradycardia, hypotension, heart failure, seizures, paralysis, and respiratory arrest have also been reported following therapy with ibogaine. Prolonged QT interval and torsades de pointes have been reported following ibogaine use. Ingestion of large amounts may induce hallucinations and cause both anxiety and apprehension. Deaths have been reported in several individuals taking ibogaine. There is inadequate data to determine if ibogaine may have been causative.

Laboratory Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with prolonged vomiting.
    C) Monitor vital signs and mental status following significant overdose.
    D) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Consider intravenous lipid therapy early for patients with ventricular dysrhythmias or hypotension. Prolonged QT interval and torsades de pointes have been reported following ibogaine use. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    C) DECONTAMINATION
    1) PREHOSPITAL: Spontaneous vomiting may occur after significant exposure. Consider activated charcoal after large ingestions and if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    2) HOSPITAL: Spontaneous vomiting may occur after significant exposure. Consider activated charcoal after large ingestions and if the overdose is recent, the patient is not vomiting, and is able to maintain airway.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with life-threatening respiratory depression, hemodynamic instability, or persistent seizures.
    E) ANTIDOTE
    1) Atropine may be useful to treat cholinergic effects such as excessive secretions, bronchorrhea, severe bradycardia with hypotension, and diarrhea.
    F) FAT EMULSION
    1) Consider intravenous lipids in patients who develop significant cardiovascular toxicity, as ibogaine is highly lipid soluble. Administer 1.5 mL/kg of 20% lipid emulsion over 2 to 3 minutes as an IV bolus, followed by an infusion of 0.25 mL/kg/min. Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion. If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources. Where possible, lipid resuscitation therapy should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.
    G) TORSADES DE POINTES
    1) Hemodynamically unstable patients require electrical cardioversion. Treat stable patients with magnesium (first-line agent) and/or atrial overdrive pacing. Correct electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia) and hypoxia, if present. MAGNESIUM SULFATE/DOSE: ADULT: 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes. An optimal dose has not been established. Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram/hour, if dysrhythmias recur. CHILDREN: 25 to 50 mg/kg diluted to 10 mg/mL; infuse IV over 5 to 15 minutes. OVERDRIVE PACING: Begin at 130 to 150 beats per minute, decrease as tolerated. Avoid class Ia (eg, quinidine, disopyramide, procainamide), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol).
    H) ENHANCED ELIMINATION PROCEDURE
    1) It is unknown if hemodialysis would be effective in overdose.
    I) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.
    3) ADMISSION CRITERIA: Patients who remain symptomatic despite treatment should be admitted. Patients with persistent mental status changes, seizures, cardiac dysrhythmias, and respiratory failure should be admitted to an ICU setting.
    4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    J) PITFALLS
    1) When managing a suspected ibogaine overdose, the possibility of multidrug involvement should be considered.
    K) TOXICOKINETICS
    1) Tmax: At 4 hours, Cmax of ibogaine ranged from 600 to 1250 ng/mL, after single oral doses of 600 mg and 800 mg, respectively. Ibogaine is highly lipophilic; ibogaine concentrations at 1 hour post administration were 100 times greater in fat, and 30 times greater in the brain, compared to plasma. Metabolism: Ibogaine is metabolized (undergoes demethylation) by cytochrome P450 2D6 to an active metabolite noribogaine (O-desmethylibogaine or 10-hydroxyibogamine). Within 15 minutes following the oral administration of ibogaine (50 mg/kg), the active metabolite (noribogaine) may be detectable in brain tissue. Renal excretion: 90% of a 20 mg/kg oral dose of ibogaine was reportedly eliminated within 24 hours. Elimination half-life: 7.5 hours.
    L) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers) or seizures (eg, meperidine).

Range Of Toxicity

    A) TOXICITY: Small doses of ibogaine (less than 50 mg) can cause stimulant, anorexigenic, euphoriant and aphrodisiac effects. Diarrhea, vomiting, trance-like visual and auditory hallucinations, altered time perception, and auditory, olfactory, and gustatory synesthesia may occur following moderate ibogaine doses (100 mg to 1 gram). All deaths that have been reported were associated with ibogaine treatment doses of 20 mg/kg or higher. A man developed vomiting, agitation, confusion, sinus bradycardia, and prolonged QT interval after ingesting 7 grams of ibogaine. He later developed several brief, self-terminating bursts of polymorphic tachycardia and torsades de pointes cardiac arrest. He recovered following supportive care, including several defibrillation efforts and placement of transcutaneous overdrive pacing.
    B) TYPICAL DOSES: Two types of ibogaine treatments have been reported: The first type is oriented toward dependency (mostly heroin dependence); typically 15 to 25 mg/kg; the other type, called the "initiatory", is oriented toward the goal of facilitating psychotherapeutic or spiritual insight; typically 8 to 12 mg/kg. In one study, patients received an average dose of ibogaine of 19.3 +/- 6.9 mg/kg (range of 6 to 29 mg/kg).

Clinical Effects

Summary Of Exposure

    A) USES: Ibogaine has been used to treat both drug (eg, heroin, methadone, cocaine) and alcohol dependency. It has been suggested that a single administration of ibogaine has the ability to either prevent or ameliorate the symptoms of drug withdrawal and reduce drug craving (usually within 1 to 2 hours). It is also used as an aperitif, aphrodisiac, CMS-stimulant, tonic, hallucinogenic, for convalescence, debility, fever, hypertension, and neurasthenia. In Central Africa (Gabon, Zaire, Cameroon), the Bwiti religious members use iboga in initiation ritual/rebirth ceremony to assist in the transition from adolescence into adulthood. In the United States, ibogaine is classified as a Schedule I drug.
    B) PHARMACOLOGY: Ibogaine, a hallucinogenic indole alkaloid, is extracted from the root of the West African shrub, Tabernanthe iboga (Apocynaceae). It inhibits cholinesterase, leading to the accumulation of synaptic acetylcholine.
    C) TOXICOLOGY: Cholinergic hyperactivity can cause slowing of the heart rate, hypotension, seizures, paralysis, and respiratory arrest. The pharmacologic effects (CNS stimulation, mild excitation, euphoria, visual and auditory hallucinations) are usually dose-dependent. The indole alkaloids, ibogaine, ibogamone, iboluteine, and tabernanthine are responsible for the hallucinogenic properties of ibogaine. Hallucinations accompanied by anxiety and apprehension are usually only experienced at the highest doses. Ibogaine can prolong QT interval, as it has central 5HT-2A agonist activity.
    D) EPIDEMIOLOGY: Overdose is rare.
    E) WITH POISONING/EXPOSURE
    1) MILD TO MODERATE TOXICITY: Ibogaine is generally well tolerated. Nausea, vomiting, ataxia, and mild tremor are the most frequent side effects reported.
    2) SEVERE TOXICITY: Bradycardia, hypotension, heart failure, seizures, paralysis, and respiratory arrest have also been reported following therapy with ibogaine. Prolonged QT interval and torsades de pointes have been reported following ibogaine use. Ingestion of large amounts may induce hallucinations and cause both anxiety and apprehension. Deaths have been reported in several individuals taking ibogaine. There is inadequate data to determine if ibogaine may have been causative.

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HEART FAILURE
    1) CASE REPORT: A 44-year-old woman died of acute heart failure approximately 4 hours after receiving a dose of ibogaine, 4.5 mg/kg PO. She had a history of hypertension, a prior myocardial infarction, severe atherosclerotic changes, and 70% to 80% stenosis of all three major coronary artery branches. It is suggested that an interaction between ibogaine and the patient's preexisting heart condition could have been a contributing factor in the fatal outcome (Alper, 2001).
    B) HYPOTENSIVE EPISODE
    1) Hypotension may occur with oral use of ibogaine (Alper, 2001; Jellin et al, 2000; Duke, 1985).
    C) BRADYCARDIA
    1) Bradycardia may occur with oral use of ibogaine (Alper, 2001; Jellin et al, 2000; Duke, 1985).
    2) CASE REPORT: A man without a history of heart disease presented with vomiting, agitation, and confusion after ingesting 7 grams of ibogaine to relieve symptoms of heroin withdrawal. On presentation, he had sinus bradycardia and marked prolongation of the QTc interval (600 ms) with several brief, self-terminating bursts of polymorphic tachycardia (VT). After developing tonic-clonic seizures, his condition deteriorated, losing cardiac output and developing torsades de pointes cardiac arrest. Defibrillation restored cardiac output, but he developed pulseless torsades de pointes again, despite supportive treatment, including IV magnesium, atropine, epinephrine, and isoproterenol therapy. Following several defibrillation and placement of transcutaneous overdrive pacing, his QT interval shortened and the ectopic ventricular activity was controlled. At this time, a temporary transvenous pacing wire replaced the transcutaneous pacemaker. He was paced at a rate of 80 beats/minute for 48 hours, without further episodes of VT. Following further supportive care, his bradycardia resolved and the QT returned to 420 ms (Asua, 2013).
    D) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) CASE REPORT: A man without a history of heart disease presented with vomiting, agitation, and confusion after ingesting 7 grams of ibogaine to relieve symptoms of heroin withdrawal. On presentation, he had sinus bradycardia and marked prolongation of the QTc interval (600 ms) with several brief, self-terminating bursts of polymorphic tachycardia (VT). After developing tonic-clonic seizures, his condition deteriorated, losing cardiac output and developing torsades de pointes cardiac arrest. Defibrillation restored cardiac output, but he developed pulseless torsades de pointes again, despite supportive treatment, including IV magnesium, atropine, epinephrine, and isoproterenol therapy. Following several defibrillation and placement of transcutaneous overdrive pacing, his QT interval shortened and the ectopic ventricular activity was controlled. At this time, a temporary transvenous pacing wire replaced the transcutaneous pacemaker. He was paced at a rate of 80 beats/minute for 48 hours, without further episodes of VT. Following further supportive care, his bradycardia resolved and the QT returned to 420 ms (Asua, 2013).
    b) CASE REPORT: A 34-year-old woman, with a medical history of heroin abuse, developed hallucinations and several seizure-like episodes after ingesting 2 grams of ibogaine powder (labeled as HCI and "total alkaloid" formulations). A day before using ibogaine, she also used heroin, cocaine, alcohol, and tobacco. An ECG revealed prolonged QT and self-terminating episodes of torsades de pointes with rigidity and clenching. In the ICU, she was intubated for mental status depression and acute respiratory failure. Following supportive care, including treatment with magnesium sulfate for prolonged QTc and torsades de pointes, her condition gradually improved and she was transferred to the inpatient psych unit. She was discharged home after 5 days of observation (Grogan et al, 2015).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) RESPIRATORY ARREST
    1) Respiratory arrest may occur with oral use of ibogaine (Alper, 2001; Jellin et al, 2000; Cienki et al, 2001; Duke, 1985).
    2) CASE REPORT: A 24-year-old woman experienced back pain and vomiting after receiving ibogaine (29 mg/kg orally) for opioid withdrawal. She suffered a respiratory arrest and died approximately 19 hours after the start of the treatment; ibogaine and noribogaine blood concentrations were 0.74 mg/L and 11.28 mg/L, respectively (Cienki et al, 2001; Alper, 2001).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) Ibogaine may cause visual and other hallucinations, often associated with severe anxiety and apprehension. Toxic doses may cause seizures, paralysis, respiratory arrest and death (Alper, 2001; Jellin et al, 2000; Duke, 1985).
    2) Agitation and confusion have been reported following ibogaine use (Asua, 2013).
    3) In one study, 30 drug-dependent subjects were assigned to one of three fixed-dose treatments: 500 mg, 600 mg, and 800 mg ibogaine. Nausea, ataxia and mild tremor were the most frequent side effects reported (Mash DC; Kovera CA; Buck BE, 1998).
    B) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) Seizures may occur with oral use of ibogaine (Jellin et al, 2000; Duke, 1985).
    b) CASE REPORT: A 34-year-old woman, with a medical history of heroin abuse, developed hallucinations and several seizure-like episodes after ingesting 2 grams of ibogaine powder (labeled as HCI and "total alkaloid" formulations). A day before using ibogaine, she also used heroin, cocaine, alcohol, and tobacco. An ECG revealed prolonged QT and self-terminating episodes of torsades de pointes with rigidity and clenching. In the ICU, she was intubated for mental status depression and acute respiratory failure. Following supportive care, including treatment with magnesium sulfate for prolonged QTc and torsades de pointes, her condition gradually improved and she was transferred to the inpatient psych unit. She was discharged home after 5 days of observation (Grogan et al, 2015).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) NAUSEA AND VOMITING
    1) Vomiting is a common adverse effect (Asua, 2013; Alper, 2001) and may occur relatively suddenly as a single episode in the first several hours of treatment (Alper, 2001).
    2) In one study, 30 drug-dependent subjects were assigned to one of three fixed-dose treatments: 500 mg, 600 mg, and 800 mg ibogaine. Nausea and mild tremor were the most frequent side effects reported (Mash DC; Kovera CA; Buck BE, 1998).
    3) In another study, the most frequent adverse effects with ibogaine (8 to 12 mg/kg doses) were nausea and tremor (Cienki et al, 2001; Alper, 2001).
    4) CASE REPORT: A 24-year-old woman experienced back pain and vomiting after receiving ibogaine (29 mg/kg PO) for narcotic withdrawal. She suffered a respiratory arrest and died approximately 19 hours after the start of the treatment; ibogaine and noribogaine blood levels were 0.74 mg/L and 11.28 mg/L, respectively (Cienki et al, 2001; Alper, 2001).
    5) CASE REPORT: A 40-year-old man experienced GI symptoms after receiving approximately 85 mg/kg of ibogaine for opioid dependence (approximately 5 grams of iboga alkaloid extract). He collapsed 24 hours after ingestion and attempts at resuscitation were unsuccessful; blood ibogaine concentration was 0.36 mg/L (Cienki et al, 2001).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with prolonged vomiting.
    C) Monitor vital signs and mental status following significant overdose.
    D) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.

Methods

    A) CHROMATOGRAPHY
    1) Gas chromatography-mass spectrometry (GC/MS) has been used to extract, derive, and detect ibogaine (Alper, 2001). The primary metabolite 12-hydroxyibogamine (noribogaine) was identified by full scan electron impact GC/MS (Mash DC; Kovera CA; Buck BE, 1998).
    2) Ibogaine and ibogamine were identified in postmortem samples and analyzed using gas chromatography combined with a tandem mass spectrometer (GC-MS/MS) after liquid-liquid extraction (LLE) (Mazoyer et al, 2013).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.1) DISPOSITION/ORAL EXPOSURE
    6.3.1.1) ADMISSION CRITERIA/ORAL
    A) Patients who remain symptomatic despite treatment should be admitted. Patients with persistent mental status changes, seizures, cardiac dysrhythmias, and respiratory failure should be admitted to an ICU setting.
    6.3.1.2) HOME CRITERIA/ORAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.1.3) CONSULT CRITERIA/ORAL
    A) Consult a poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.1.5) OBSERVATION CRITERIA/ORAL
    A) Patients with a deliberate overdose, and those who are symptomatic should be observed with frequent monitoring of vital signs. Patients that remain asymptomatic can be discharged.

Monitoring

    A) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    B) Monitor serum electrolytes in patients with prolonged vomiting.
    C) Monitor vital signs and mental status following significant overdose.
    D) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    E) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Vomiting may occur after significant exposure. Activated charcoal should be considered after large ingestions.
    B) ACTIVATED CHARCOAL
    1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION
    a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).
    1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
    2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.2) PREVENTION OF ABSORPTION
    A) Spontaneous vomiting may occur after significant exposure. Activated charcoal should be considered after large ingestions.
    B) ACTIVATED CHARCOAL
    1) CHARCOAL ADMINISTRATION
    a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.
    2) CHARCOAL DOSE
    a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).
    1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).
    b) ADVERSE EFFECTS/CONTRAINDICATIONS
    1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
    2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    6.5.3) TREATMENT
    A) SUPPORT
    1) MANAGEMENT OF MILD TO MODERATE TOXICITY
    a) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids.
    2) MANAGEMENT OF SEVERE TOXICITY
    a) Treatment is symptomatic and supportive. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Consider intravenous lipid therapy early for patients with ventricular dysrhythmias or hypotension. Prolonged QT interval and torsades de pointes have been reported following ibogaine use. Treat torsades de pointes with IV magnesium sulfate, and correct electrolyte abnormalities, overdrive pacing may be necessary.
    B) MONITORING OF PATIENT
    1) Plasma concentrations are not readily available or clinically useful in the management of overdose.
    2) Monitor serum electrolytes in patients with prolonged vomiting.
    3) Monitor vital signs and mental status following significant overdose.
    4) Institute continuous cardiac monitoring and obtain an ECG in symptomatic patients.
    5) Monitor pulse oximetry and/or arterial blood gases in patients with respiratory signs or symptoms.
    C) SEIZURE
    1) SUMMARY
    a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
    b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
    c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).
    2) DIAZEPAM
    a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
    b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .
    3) NO INTRAVENOUS ACCESS
    a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
    b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).
    4) LORAZEPAM
    a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
    b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
    c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2009; Chin et al, 2008).
    5) PHENOBARBITAL
    a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
    b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
    c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
    d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
    e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
    f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).
    6) OTHER AGENTS
    a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):
    1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
    2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
    3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
    4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).
    D) HYPOTENSIVE EPISODE
    1) SUMMARY
    a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.
    2) DOPAMINE
    a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
    3) NOREPINEPHRINE
    a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
    b) DOSE
    1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
    2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
    3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).
    E) ATROPINE
    1) Atropine may be useful to treat cholinergic effects such as excessive secretions, bronchorrhea, severe bradycardia with hypotension, and diarrhea.
    F) FAT EMULSION
    1) Consider intravenous lipids in patients who develop significant cardiovascular toxicity, as ibogaine is highly lipid soluble.
    2) Intravenous lipid emulsion (ILE) has been effective in reversing severe cardiovascular toxicity from local anesthetic overdose in animal studies and human case reports. Several animal studies and human case reports have also evaluated the use of ILE for patients following exposure to other drugs. Although the results of these studies are mixed, there is increasing evidence that it can rapidly reverse cardiovascular toxicity and improve mental function for a wide variety of lipid soluble drugs. It may be reasonable to consider ILE in patients with severe symptoms who are failing standard resuscitative measures (Lavonas et al, 2015).
    3) The American College of Medical Toxicology has issued the following guidelines for lipid resuscitation therapy (LRT) in the management of overdose in cases involving a highly lipid soluble xenobiotic where the patient is hemodynamically unstable, unresponsive to standard resuscitation measures (ie, fluid replacement, inotropes and pressors). The decision to use LRT is based on the judgement of the treating physician. When possible, it is recommended these therapies be administered with the consultation of a medical toxicologist (American College of Medical Toxicology, 2016; American College of Medical Toxicology, 2011):
    a) Initial intravenous bolus of 1.5 mL/kg 20% lipid emulsion (eg, Intralipid) over 2 to 3 minutes. Asystolic patients or patients with pulseless electrical activity may have a repeat dose, if there is no response to the initial bolus.
    b) Follow with an intravenous infusion of 0.25 mL/kg/min of 20% lipid emulsion (eg, Intralipid). Evaluate the patient's response after 3 minutes at this infusion rate. The infusion rate may be decreased to 0.025 mL/kg/min (ie, 1/10 the initial rate) in patients with a significant response. This recommendation has been proposed because of possible adverse effects from very high cumulative rates of lipid infusion. Monitor blood pressure, heart rate, and other hemodynamic parameters every 15 minutes during the infusion.
    c) If there is an initial response to the bolus followed by the re-emergence of hemodynamic instability during the lowest-dose infusion, the infusion rate may be increased back to 0.25 mL/kg/min or, in severe cases, the bolus could be repeated. A maximum dose of 10 mL/kg has been recommended by some sources.
    d) Where possible, LRT should be terminated after 1 hour or less, if the patient's clinical status permits. In cases where the patient's stability is dependent on continued lipid infusion, longer treatment may be appropriate.
    G) TORSADES DE POINTES
    1) Prolonged QT interval and torsades de pointes have been reported following ibogaine use (Asua, 2013).
    2) SUMMARY
    a) Withdraw the causative agent. Hemodynamically unstable patients with Torsades de pointes (TdP) require electrical cardioversion. Emergent treatment with magnesium (first-line agent) or atrial overdrive pacing is indicated. Detect and correct underlying electrolyte abnormalities (ie, hypomagnesemia, hypokalemia, hypocalcemia). Correct hypoxia, if present (Drew et al, 2010; Neumar et al, 2010; Keren et al, 1981; Smith & Gallagher, 1980).
    b) Polymorphic VT associated with acquired long QT syndrome may be treated with IV magnesium. Overdrive pacing or isoproterenol may be successful in terminating TdP, particularly when accompanied by bradycardia or if TdP appears to be precipitated by pauses in rhythm (Neumar et al, 2010). In patients with polymorphic VT with a normal QT interval, magnesium is unlikely to be effective (Link et al, 2015).
    3) MAGNESIUM SULFATE
    a) Magnesium is recommended (first-line agent) for the prevention and treatment of drug-induced torsades de pointes (TdP) even if the serum magnesium concentration is normal. QTc intervals greater than 500 milliseconds after a potential drug overdose may correlate with the development of TdP (Charlton et al, 2010; Drew et al, 2010). ADULT DOSE: No clearly established guidelines exist; an optimal dosing regimen has not been established. Administer 1 to 2 grams diluted in 10 milliliters D5W IV/IO over 15 minutes (Neumar et al, 2010). Followed if needed by a second 2 gram bolus and an infusion of 0.5 to 1 gram (4 to 8 mEq) per hour in patients not responding to the initial bolus or with recurrence of dysrhythmias (American Heart Association, 2005; Perticone et al, 1997). Rate of infusion may be increased if dysrhythmias recur. For persistent refractory dysrhythmias, a continuous infusion of up to 3 to 10 milligrams/minute in adults may be given (Charlton et al, 2010).
    b) PEDIATRIC DOSE: 25 to 50 milligrams/kilogram diluted to 10 milligrams/milliliter for intravenous infusion over 5 to 15 minutes up to 2 g (Charlton et al, 2010).
    c) PRECAUTIONS: Use with caution in patients with renal insufficiency.
    d) MAJOR ADVERSE EFFECTS: High doses may cause hypotension, respiratory depression, and CNS toxicity (Neumar et al, 2010). Toxicity may be observed at magnesium levels of 3.5 to 4.0 mEq/L or greater (Charlton et al, 2010).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respiratory rate, motor strength, deep tendon reflexes, serum magnesium, phosphorus, and calcium concentrations (Prod Info magnesium sulfate heptahydrate IV, IM injection, solution, 2009).
    4) OVERDRIVE PACING
    a) Institute electrical overdrive pacing at a rate of 130 to 150 beats per minute, and decrease as tolerated. Rates of 100 to 120 beats per minute may terminate torsades (American Heart Association, 2005). Pacing can be used to suppress self-limited runs of TdP that may progress to unstable or refractory TdP, or for override refractory, persistent TdP before the potential development of ventricular fibrillation (Charlton et al, 2010). In a case series overdrive pacing was successful in terminating TdP associated with bradycardia and drug-induced QT prolongation (Neumar et al, 2010).
    5) POTASSIUM REPLETION
    a) Potassium supplementation, even if serum potassium is normal, has been recommended by many experts (Charlton et al, 2010; American Heart Association, 2005). Supplementation to supratherapeutic potassium concentrations of 4.5 to 5 mmol/L has been suggested, although there is little evidence to determine the optimal range in dysrhythmia (Drew et al, 2010; Charlton et al, 2010).
    6) ISOPROTERENOL
    a) Isoproterenol has been successful in aborting torsades de pointes that was resistant to magnesium therapy in a patient in whom transvenous overdrive pacing was not an option (Charlton et al, 2010) and has been successfully used to treat torsades de pointes associated with bradycardia and drug induced QT prolongation (Keren et al, 1981; Neumar et al, 2010). Isoproterenol may have a limited role in pharmacologic overdrive pacing in select patients with drug-induced torsades de pointes and acquired long QT syndrome (Charlton et al, 2010; Neumar et al, 2010). Isoproterenol should be avoided in patients with polymorphic VT associated with familial long QT syndrome (Neumar et al, 2010).
    b) DOSE: ADULT: 2 to 10 micrograms/minute via a continuous monitored intravenous infusion; titrate to heart rate and rhythm response (Neumar et al, 2010).
    c) PRECAUTIONS: Correct hypovolemia before using; contraindicated in patients with acute cardiac ischemia (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    1) Contraindicated in patients with preexisting dysrhythmias; tachycardia or heart block due to digitalis toxicity; ventricular dysrhythmias that require inotropic therapy; and angina. Use with caution in patients with coronary insufficiency (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) MAJOR ADVERSE EFFECTS: Tachycardia, cardiac dysrhythmias, palpitations, hypotension or hypertension, nervousness, headache, dizziness, and dyspnea (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    e) MONITORING PARAMETERS: Monitor heart rate and rhythm, blood pressure, respirations and central venous pressure to guide volume replacement (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    7) OTHER DRUGS
    a) Mexiletine, verapamil, propranolol, and labetalol have also been used to treat TdP, but results have been inconsistent (Khan & Gowda, 2004).
    8) AVOID
    a) Avoid class Ia antidysrhythmics (eg, quinidine, disopyramide, procainamide, aprindine), class Ic (eg, flecainide, encainide, propafenone) and most class III antidysrhythmics (eg, N-acetylprocainamide, sotalol) since they may further prolong the QT interval and have been associated with TdP.

Enhanced Elimination

    A) HEMODIALYSIS
    1) It is unknown if hemodialysis would be effective in overdose.

Range Of Toxicity

Summary

    A) TOXICITY: Small doses of ibogaine (less than 50 mg) can cause stimulant, anorexigenic, euphoriant and aphrodisiac effects. Diarrhea, vomiting, trance-like visual and auditory hallucinations, altered time perception, and auditory, olfactory, and gustatory synesthesia may occur following moderate ibogaine doses (100 mg to 1 gram). All deaths that have been reported were associated with ibogaine treatment doses of 20 mg/kg or higher. A man developed vomiting, agitation, confusion, sinus bradycardia, and prolonged QT interval after ingesting 7 grams of ibogaine. He later developed several brief, self-terminating bursts of polymorphic tachycardia and torsades de pointes cardiac arrest. He recovered following supportive care, including several defibrillation efforts and placement of transcutaneous overdrive pacing.
    B) TYPICAL DOSES: Two types of ibogaine treatments have been reported: The first type is oriented toward dependency (mostly heroin dependence); typically 15 to 25 mg/kg; the other type, called the "initiatory", is oriented toward the goal of facilitating psychotherapeutic or spiritual insight; typically 8 to 12 mg/kg. In one study, patients received an average dose of ibogaine of 19.3 +/- 6.9 mg/kg (range of 6 to 29 mg/kg).

Therapeutic Dose

    7.2.1) ADULT
    A) GENERAL
    1) In August of 1993, FDA Advisory Panel meeting was held to formally consider Investigational New Drug Application; approval was given for human trials with ibogaine dosage concentrations of 1, 2, 5 milligrams/kilogram. However, the phase I dose escalation study was eventually suspended (Alper, 2001).
    2) Two types of ibogaine treatments have been reported: The first type is oriented toward dependency (mostly heroin dependence); typically 15 to 25 milligrams/kilogram; the other type, called the "initiatory", is oriented toward the goal of facilitating psychotherapeutic or spiritual insight; typically 8 to 12 milligrams/kilogram (Frenken, 2001; Alper, 2001). In non-hospital settings, ibogaine has generally been given to patients as a single oral dose, usually in the morning (Alper, 2001).
    3) In one study, patients received an average dose of ibogaine of 19.3 +/- 6.9 mg/kg (range of 6 to 29 mg/kg) (Alper et al, 1999). In another study, patients were assigned to one of three fixed-dose (500, 600, or 800 milligrams) ibogaine hydrochloride for the indication of opioid withdrawal (Mash et al, 2000).
    4) The following doses of pure ibogaine hydrochloride have also been reported: 10 milligrams/kilogram for men and 9 milligrams/kilogram for women. Since the "Indra iboga extract" is believed to be approximately one quarter the strength of pure hydrochloride, patients usually require roughly four times the amount. The "Indra" product is known to induce more vomiting than the hydrochloride (N Sandberg , 2001).
    5) TEST DOSE - Approximately 24 hours before the main dose of ibogaine, a 100-milligram dose is usually administered to the patient to test for a hypersensitivity reaction (N Sandberg , 2001).

Minimum Lethal Exposure

    A) All deaths occurred with ibogaine treatment doses of 20 mg/kg or higher (N Sandberg , 2001).
    B) CASE REPORT: A 27-year-old man who was undergoing a methadone-based substitution treatment for 4 years, died 12 hours after ingesting a teaspoonful of powdered iboga root (7.2% ibogaine and 0.6% ibogamine) with methadone and diazepam. Postmortem ibogaine concentrations in blood, peripheral blood, urine, and gastric fluid samples were 0.65 mcg/mL (650 ng/mL), 1.27 mcg/mL (1270 ng/mL), 1.7 mcg/mL (1700 ng/mL), 53.5 mcg/mL (53,500 ng/mL), respectively. There were about 108 to 144 mg of ibogaine and 9 to 12 mg of ibogamine in a teaspoonful of 1.5 to 2 grams of the powder (Mazoyer et al, 2013).
    C) CASE REPORT: A 24-year-old woman experienced back pain and vomiting after receiving ibogaine (29 mg/kg PO) for opioid withdrawal. She suffered a respiratory arrest and died approximately 19 hours after the start of the treatment; ibogaine and noribogaine blood concentrations were 0.74 mg/L and 11.28 mg/L, respectively (Cienki et al, 2001; Alper, 2001).
    D) CASE REPORT: A 40-year-old man experienced GI symptoms after receiving approximately 85 mg/kg of ibogaine for opioid dependence (approximately 5 grams of iboga alkaloid extract). He collapsed approximately 24 hours postingestion and attempts at resuscitation were unsuccessful; blood ibogaine concentration was 0.36 mg/L (Cienki et al, 2001).

Maximum Tolerated Exposure

    A) Small doses of ibogaine (less than 50 mg) can cause stimulant, anorexigenic, euphoriant and aphrodisiac effects. Diarrhea, vomiting, trance-like visual and auditory hallucinations, altered time perception, and auditory, olfactory, and gustatory synesthesia may occur following moderate ibogaine doses (100 mg to 1 gram) (Mazoyer et al, 2013).
    B) CASE REPORT: A man developed vomiting, agitation, confusion, sinus bradycardia, and prolonged QT interval after ingesting 7 grams of ibogaine. He later developed several brief, self-terminating bursts of polymorphic tachycardia and torsades de pointes cardiac arrest. He recovered following supportive care, including several defibrillation efforts and placement of transcutaneous overdrive pacing (Asua, 2013).
    C) CASE REPORT: A 34-year-old woman, with a medical history of heroin abuse, developed hallucinations and several seizure-like episodes after ingesting 2 grams of ibogaine powder (labeled as HCI and "total alkaloid" formulations). A day before using ibogaine, she also used heroin, cocaine, alcohol, and tobacco. An ECG revealed prolonged QT and self-terminating episodes of torsades de pointes with rigidity and clenching. In the ICU, she was intubated for mental status depression and acute respiratory failure. Following supportive care, including treatment with magnesium sulfate for prolonged QTc and torsades de pointes, her condition gradually improved and she was transferred to the inpatient psych unit. She was discharged home after 5 days of observation (Grogan et al, 2015).

Serum Plasma Blood Concentrations

    7.5.2) TOXIC CONCENTRATIONS
    A) TOXIC CONCENTRATION LEVELS
    1) POSTMORTEM: A 27-year-old man who was undergoing a methadone-based substitution treatment for 4 years, died 12 hours after ingesting a teaspoonful of powdered iboga root (7.2% ibogaine and 0.6% ibogamine) with methadone and diazepam. Postmortem ibogaine concentrations in blood, peripheral blood, urine, and gastric fluid samples were 0.65 mcg/mL (650 ng/mL), 1.27 mcg/mL (1270 ng/mL), 1.7 mcg/mL (1700 ng/mL), 53.5 mcg/mL (53,500 ng/mL), respectively. There were about 108 to 144 mg of ibogaine and 9 to 12 mg of ibogamine in a teaspoonful of 1.5 to 2 grams of the powder (Mazoyer et al, 2013).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) ANIMAL DATA
    1) LD50- (INTRAPERITONEAL)MOUSE:
    a) 175 mg/kg (Alper, 2001)
    2) LD50- (INTRAPERITONEAL)RAT:
    a) 145 mg/kg (Alper, 2001)
    3) LD50- (ORAL)RAT:
    a) 482 mg/kg (RTECS , 2001)

Pharmacology Toxicology

Pharmacologic Mechanism

    A) Ibogaine inhibits cholinesterase, leading to the accumulation of synaptic acetylcholine and cholinergic hyperactivity (slowing of the heart rate, hypotension, convulsions, paralysis, and respiratory arrest). The pharmacologic effects (CNS stimulation - mild excitation, euphoria, visual and auditory hallucinations) are usually dose-dependent. The indole alkaloids, ibogaine, ibogamone, iboluteine, and tabernanthine are responsible for the hallucinogenic properties of iboga. Hallucinations accompanied by anxiety and apprehension are usually only experienced at the highest doses (Jellin et al, 2000; Glick & Maisonneuve, 1998; Anon, 1994).
    B) In addition, it exhibits nicotinic, and N-methyl-D-aspartate (NMDA) antagonism and has kappa agonist properties. Tabernanthine, a constituent, demonstrates cardiac conduction effects characteristic of a calcium channel antagonist (Jellin et al, 2000; Glick & Maisonneuve, 1998; Anon, 1994).
    C) Ibogaine has been used to reduce drug-craving and opioid withdrawal signs and symptoms (usually within 1 to 2 hours) (Alper, 2001).
    1) SUBJECTIVE EFFECTS (Alper, 2001; Mash DC; Kovera CA; Buck BE, 1998; N Sandberg , 2001)
    a) ACUTE PHASE - Onset is within 1 to 3 hours of ingestion, with a duration of 4 to 8 hours; also called "oneirophrenic" or "dream-creating" phase; user experiences dream-like visions; active period of visualizations (usually actual memories).
    b) EVALUATIVE PHASE "PROCESSING OR COGNITIVE PHASE" - Approximately 4 to 8 hours after ingestion, with a duration of 8 to 20 hours; high levels of mental activity with the interpretation of material revealed in the first phase.
    c) RESIDUAL STIMULATION PHASE - Approximately 12 to 24 hours after ingestion, with a duration of 24 to 72 hours or longer; return of normal allocation of attention to the external environment.

Toxicologic Mechanism

    A) Ibogaine can prolong QT interval, as it has central 5HT-2A agonist activity (Asua, 2013).

Physicochemical

Physical Characteristics

    A) Ibogaine is soluble in ethanol, ether, chloroform, acetone and benzene, but it is practically insoluble in water. Ibogaine hydrochloride is soluble in water, methanol, and ethanol, slightly soluble in acetone and chloroform, and practically insoluble in ether (Alper, 2001).

Molecular Weight

    A) 310.44 (Alper, 2001)

References

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