Cardiac Arrest after Ibogaine Ingestion

Vlaanderen et al., J Clin Toxicol 2013, S:12 http://dx.doi.org/10.4172/2161-0495.S12-005

Clinical Toxicology Research Case Report Article

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Cardiac Arrest after Ibogaine Ingestion Vlaanderen L1*, Martial LC2*, van der Voort PHJ3, Oosterwerff E4, Somsen GA4 and Franssen EJF2 Onze Lieve Vrouwe Gasthuis, Department of Emergency Medicine, Amsterdam, The Netherlands Onze Lieve Vrouwe Gasthuis, Department of Clinical Pharmacy, Amsterdam, The Netherlands 3 Onze Lieve Vrouwe Gasthuis, Department of Intensive care, Amsterdam, The Netherlands 4 Onze Lieve Vrouwe Gasthuis, Department of Cardiology, Amsterdam, The Netherlands 1 2

Abstract Introduction: Ibogaine is an indole alkaloid derived from the bark of the root of the plant Tabernanthe Ibogaine. It has been used for its hallucinogenic effects, and studied for its potential anti-addictional properties. However, potential fatal side effects are associated with this drug. We present the clinical and pharmacokinetic data of a healthy 26 year old man who suffered from a cardiac arrest due to ventricular fibrillation after ingestion of ibogaine. Methods: During admission serum concentrations of ibogaine were measured with LC-MS/MS. Routine toxicological testing for illicit drugs was also performed. Results: The highest serum concentration of ibogaine measured was 948 ug/L. A calculation with a presumed Vd of 13 L/kg indicated that there was an estimated amount of 910 mg ibogaine in the body. Additional toxicological screening revealed no other intoxications. On the ECG, prolonged QTc intervals were observed with a maximum of 663 msec. Conclusion: We present a case report of a 26 year old man who developed ventricular fibrillation and severe prolongation of the QTc interval after ingestion of ibogaine. This resulted in permanent neurological disability. Since the intake of ibogaine can result in life-threatening conditions its use should be strongly discouraged.

Keywords: Tabernanthe Ibogaine; Intoxication; Post anoxic encephalopathy

Ibogaine;

Noribogaine;

Introduction Ibogaine is an indole alkaloid (Figure 1) derived from the bark of the root of the West African plant Tabernanthe Ibogaine. The main alkaloid in this rootbark is predominantly ibogaine (±80%). Other constituents, such as ibogaline, ibogamine and tabernanthine are less abundant [1,2]. The main active metabolite is noribogaine. The rootbark is used by the indigenous people for its hallucinogenic properties, as well as to reduce hunger and fatigue. Since decades there is special interest for its pretended aanti-addictive properties [3-6]. It is mostly used in a single dose, and there are no reports of chronic use [7]. For an overview of the pharmacological and toxicological properties of ibogaine and noribogaine (Table 1). We report a patient with cardiac arrest due to ventricular fibrillation after ingestion of ibogaine including an extensive toxic kinetic and toxicodymamic evaluation in this patient.

Case Report

after an out of hospital cardiac arrest, based on ventricular fibrillation, after ingestion of 2400 mg ibogaine for a spiritual experience. Basic life support was started immediately after the arrest. Defibrillation was performed four times. Return of spontaneous circulation occurred after 20 minutes. On admission, he was intubated and mechanically ventilated. His Glasgow Coma score was E1M1V1 (tube), though sedated with midazolam and propofol. Physical examination revealed no abnormalities with normal oxygen saturation and an arterial blood pressure of 110/60 mmHg. The ECG showed a slightly prolonged QTc (467 ms). Subsequent ECGs (Figure 2) during admission showed a prolonged QT interval during the first 32 hours post event, with a maximum QTc of 663 ms 18 hours after his arrest. A cardiological screening prior to the ibogaine treatment was obtained 9 days earlier. This was recommended by the ibogaine clinic which our patient visited. The ECG made at this visit showed no abnormalities with a normal QTc (428ms). Blood analysis revealed a mild hypomagnesemia (0.61 mmol/l; ref range 0.70-1.00 mmol/l), hypocalcaemia (2.06 mmol/l;ref range 2.20 – 2.60 mmol/l) and hypophosphatemia (0.62 mmol/l; ref range 0.70-1,50 mmol/l). The toxicological screening showed the presence

A previously healthy 26 year old man was presented in our hospital

R

8

11 12

10

9

13

15

17

14

N H

16

7

H 18

*Corresponding authors: Vlaanderen L, Onze Lieve Vrouwe Gasthuis, Department of Emergency Medicine, Amsterdam, The Netherlands, E-mail: [email protected]

19 6

Martial LC, Onze Lieve Vrouwe Gasthuis, Department of Clinical Pharmacy, Amsterdam, The Netherlands

5

H

1

4 3

20

CH3 21

2

R = OH R = OCH3

Noribogaine Ibogaine

Figure 1: Chemical structure of ibogaine and noribogaine (adapted from [2]).

J Clin Toxicol ISSN: 2161-0495 JCT, an open access journal

Received January 28, 2012; Accepted June 04, 2013; Published June 06, 2013 Citation: Vlaanderen L, Martial LC, van der Voort PHJ, Oosterwerff E, Somsen GA (2013) Cardiac Arrest after Ibogaine Ingestion. J Clin Toxicol S12: 005. doi:10.4172/2161-0495.S12-005 Copyright: © 2013 Vlaanderen L, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Special • Issue 2013

Citation: Vlaanderen L, Martial LC, van der Voort PHJ, Oosterwerff E, Somsen GA (2013) Cardiac Arrest after Ibogaine Ingestion. J Clin Toxicol S12: 005. doi:10.4172/2161-0495.S12-005

Page 2 of 4

of benzodiazepines (which he had received during resuscitation in the ED) and ibogaine, but no other drugs.

spectra of the reference substance of ibogaine, the mass transitions of the Selected Reaction Monitoring (SRM) were as follows: parent 311,2 m/z to daughter 122,1 m/z. The collision energy was 32 mV. The internal standard was disopyramid, with a SRM transition value of the parent 340,1 m/z to daughter 239,0 m/z and a collision energy of 17 V. Injection volume was 1 µL.

The post resuscitation treatment consisted of mild therapeutic hypothermia with a core temperature between 32 and 34 degrees Celsius for 24 hours, mechanical ventilation and shock resuscitation. He developed seizures for which he was treated with anti-epileptics (phenytoin, valproic acid and levetiracetam). After 8 days he was transferred to another hospital. At that moment the Glasgow coma score was E1M2Vtube without sedation.

Toxicokinetic Evaluation Figure 3 shows the serum concentration time-curve of ibogaine in our patient. The highest level measured was 948 µg/L (Cmax). A calculation with a theoretical Vd of 13 L/kg (in steady state circumstances) indicates that there was an estimated amount of 910 mg ibogaine [3,4]. This is less than the expected 2400 mg. This can be explained by various observations. Firstly, the Cmax is supposed to be much higher than observed due to a delay in blood sampling. The first blood sample was taken about five hours post-ingestion. At that time, a great part is supposed to be metabolized to noribogaine. Intake of a pharmacological dose results in a Tmax of 2 hours and half life of 6-8 hours [3]. Secondly, toxicokinetics may not be accurate in measuring the actual plasma concentration due to the large intake of ibogaine (2400 mg). Especially, alterations in absorption, distribution

Several weeks later he was awake and able to communicate with his environment, but permanent neurologic deficits remained as well as loss of vision, most likely due to postanoxic encephalopathy.

Materials and Methods Blood samples were taken on the day of admission and on day 2, 3, 4 and 6. Serum concentrations of ibogaine were measured with LCMS/MS (TSQ Quantum Discovery Max) with an Ion Max ESI probe in positive polarity. The mobile phase consisted of 70% pH 3.2 10 mM ammonium acetate buffer and 30% acetonitrile. According to the mass Receptor/ neurotransmitter

Affinity ibogaine (IC50, μM)

Affinity noribogaine (IC50, μM)

Action in CNS

Clinical effect

0.59

0.04

Reuptake blocker

Nausea, vomiting

11

0.16

Agonist

Respiratory depression, bradycardia

Serotonergic 5-HT Opiodergic μ-receptors κ1-receptor

25

4.2

Partial agonist

Miosis,diuresis

κ2-receptor

23.8

92.3

Partial agonist

Dysphoria

5.2

31.4

Channel blocker

Glutaminergic NMDA AChE

Inhibitor

Extracellular dopamine

Decrease in dopamine levels

Possibly leading to ataxia, tremors

Abbreviations: 5-HT, serotonin; NMDA, N-methyl-D-aspartate; AChE, acetylcholinesterase; IC50, half maximal inhibitory concentration [6,8,9,10] Table 1: Overview of pharmacological and toxicologic properties of ibogaine and noribogaine in the central nervous system.

Figure 2: First available ECG, made 4, 5 hrs after cardiac arrest (QTc 568 ms).




Page 3 of 4

Plasma concentration time curve of iboga in patient X measured with LC MS/MS

1200

Plasma concentration (ug/L)

1000 800 600 400

Thus far, there is no specific antidote for ibogaine intoxications. Active charcoal can be considered. Supportive care in case of seizures and hypotension should be given. Recently, treatment with intralipid infusions (20%) has been described for overdoses of a wide variety of lipophilic drugs as well as accidental intravasation of local anaesthetics [19]. Intralipid is an intravenous infusion of a fatty emulsion, to treat severe and potentially fatal poisonings/ drug toxicities. Ibogaine and noribogaine have lipophilic properties, resulting in penetration into the brain. Intralipid infusions may be considered in cases of overdoses.

Conclusion

200 0 0

20

40

60

80 100 120 140 160 Time after intake of iboga (hours)

180

Figure 3: Plasma concentration time curve of ibogaine in our patient.

and metabolism may occur in case of a high ibogaine dose. A possible reduction in the absorption of ibogaine can be explained by its affinity for the µ-opioid receptor, which may result in delayed gastric emptying. Moreover, the bioavailability of ibogaine has never been investigated in a clinical setting. Thirdly, the purity of ibogaine may have influenced the plasma concentration. Ibogaine is extracted from the root of Tabernanthe Ibogaine; this manufacturing method results in products with different purities. The different alkaloids that are present in the iboga mixture may also have contributed to the diverse toxicological effects. Further, impaired CYP2D6 expression (poor metabolizer) may have resulted in relatively high serum levels of ibogaine.

Discussion We describe a previously healthy 26 year old man with an out of hospital cardiac arrest after ingesting ibogaine. Various intoxications with ibogaine have been described, some with a fatal outcome. The amount of ibogaine ingested in these reported cases varied between 300 – 3500 mg [11-14]. Our patient ingested 2400 mg (35 mg/kg). Ibogaine has a t1/2 of 6-8 hours and is extensively metabolized by cytochrome P450 2D6 enzyme to the active metabolite des-methylibogaine (noribogaine) [15,16] which has a longer t1/2 [4]. In vivo experiments have shown the binding capacities of both ibogaine and noribogaine on the central nerve system. These are predominantly serotonergic, opioidergic and glutaminergic, resulting in respectively inhibition of 5HT-reuptake, (partial) agonistic properties on the µ and κ-opioid receptors and calcium channel blocking effects [3]. Some effects of ibogaine suggest a cholinergic hyperactivity (for example due to inhibition of cholinesterase): bradycardia, hypotension, convulsions, paralysis and respiratory effects. Recent research could not establish this hypothesis [17]. In our patient, we propose a direct relationship between the ventricular fibrillation and the ingestion of ibogaine, possibly due to sympathetic or anticholinergic hyperactivity. This could decrease the refractory period, induce triggered activity and early after potentials which are the triggers for ventricular tachycardia/fibrillation and may lead to prolonged QTc. The seizures that followed can be explained by two causes; postanoxic encephalopathy or a direct effect of noribogaine since this metabolite has a longer half life and penetrates the blood-brain barrier more extensively than the parent compound ibogaine [18]. J Clin Toxicol ISSN: 2161-0495 JCT, an open access journal

Thus far, there are scarce data about the pharmacological effects and the possible risks of ibogaine. We present a case report of a 26 year old man who developed ventricular fibrillation and a severely prolonged QTc interval after ingestion of ibogaine, which suggests a causal relation. Toxicological screening revealed no other intoxications apart from ibogaine intake. The pharmacological profile of ibogaine is complex. A better understanding of this drug is important not only to improve medical treatment, but also to prevent the serious and possible life threatening events as we described. Ibogaine is a drug which is used for spiritual experiences and in some countries as an anti-addictive drug. The drug is not well known and the use is not wide spread, however, the effects can be devastating. Therefore its use should be strongly discouraged.

Declaration of Interest The authors report no declaration of interest. The authors alone are responsible for the content and writing of this paper. References 1. Zubaran C (2000) Ibogaine and norIbogaine: comparing parent compound to metabolite. CNS Drug Rev 6: 219-240. 2. Bruneton J (1999) Pharmacognosie, phytochimie, plantes médicinales (3rd Edn), Tec et Doc dicales internationales, Paris. 3. Mash DC, Kovera CA, Pablo J, Tyndale R, Ervin FR, et al. (2001) Ibogaine in the treatment of heroin withdrawal. Alkaloids Chem Biol 56: 155-171. 4. Mash DC, Kovera CA, Pablo J, Tyndale RF, Ervin FD, et al. (2000) Ibogaine: complex pharmacokinetics, concerns for safety, and preliminary efficacy measures. Ann N Y Acad Sci 914: 394-401. 5. Alper KR, Lotsof HS, Frenken GM, Luciano DJ, Bastiaans J (1999) Treatment of acute opioid withdrawal with ibogaine. Am J Addict 8: 234-242. 6. Mash DC, Staley JK, Baumann MH, Rothman RB, Hearn WL (2000) Ibogaine in acute opioid withdrawal. An open label case series. Ann N Y Acad Sci 909: 257-259. 7. Alper KR (2001) Ibogaine: a review. Alkaloids Chem Biol 56: 1-38. 8. Goodman and Gilman’s (2006) The Pharmalogical basis of Therapeutics, (11thedn), The McGraw- Hill companies, Inc. United States of America. 9. Maciulaitis R, Kontrimaviciute V, Bressolle FM, Briedis V (2008) Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review. Hum Exp Toxicol 27: 181-194. 10. Chèze M, Lenoan A, Deveaux M, Pépin G (2008) Determination of ibogaine and noribogaine in biological fluids and hair by LC-MS/MS after Tabernanthe iboga abuse Iboga alkaloids distribution in a drowning death case. Forensic Sci Int 176: 58-66. 11. Alper KR, StajiÄ‡ M, Gill JR (2012) Fatalities temporally associated with the ingestion of ibogaine. J Forensic Sci 57: 398-412. 12. Baumann MH, Rothman RB, Pablo JP, Mash DC (2001) In vivo neurobiological effects of ibogaine and its O-desmethyl metabolite, 12-hydroxyibogamine (noribogaine), in rats. J Pharmacol Exp Ther 297: 531-539. 13. Pleskovic A, Gorjup V, Brvar M, Kozelj G (2012) Ibogaine-associated ventricular tachyarrhythmias. Clin Toxicol (Phila) 50: 157.



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15. Mash DC, Staley JK, Baumann MH, Rothman RB, Hearn WL (1995) Identification of a primary metabolite of ibogaine that targets serotonin transporters and elevates serotonin. Life Sci 57: PL45-50.

18. KontrimaviciÅ«te V, Mathieu O, Mathieu-DaudÃ© JC, Vainauskas P, Casper T, et al. (2006) Distribution of ibogaine and noribogaine in a man following a poisoning involving root bark of the Tabernanthe iboga shrub. J Anal Toxicol 30: 434-440.

16. Mash DC, Kovera CA, Buck BE, Norenberg MD, Shapshak P, et al. (1998) Medication development of ibogaine as a pharmacotherapy for drug dependence. Ann N Y Acad Sci 844: 274-292.

19. Cave G, Harvey M (2009) Intravenous lipid emulsion as antidote beyond local anesthetic toxicity: a systematic review. Acad Emerg Med 16: 815-824.

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