Federico Massariello, Antonio Alessandro Marino
Ibogaine, the most extensively studied iboga alkaloid, occurs in the root bark of the West African Apocynaceous shrub Tabernanthe iboga Baill. In Gabon, eboga, the scrapings of the root bark, has been used as a psychopharmacological sacrament in the Bwiti religion for several centuries.
Ibogaine is a naturally occurring alkaloid derived from the roots of the rain forest shrub Tabernanthe iboga. The plant is mainly found in West and Central Africa and has long been used in rituals and to
fight fatigue, hunger and thirst. In the last decades it drew the attention of the Western world for its potential to inhibit withdrawal symptoms associated with weaning from drugs. Ibogaine has previously been reported to have central nervous system (CNS) stimulant, anxiogenic, and hallucinogenic properties. T. iboga was first introduced to the Western world in 1864, when samples of the plant were brought to France from Gabon, and its ritual usage was first described in print in 1885. Ibogaine was first crystallized from extracts of the shrub’s root bark in 1901, and its pharmacodynamic properties were first explored in the first decade of the 20th Century; during that same time was recommended as a treatment for “asthenia” at a dosage of 10 to 30 mg per day. From 1939 to 1970 ibogaine was marketed in France as “Lambarene,” a “neuromuscular stimulant” in the form of 8 mg tablets, for conditions including fatigue, depression, and infectious disease.
Nowadays ground, dried iboga root bark is sometimes used clinically by ibogaine providers in Mexico and elsewhere, as is an alkaloid extract of the root bark, in treatments for indications of substance use disorders. However, the form most commonly used at ibogaine clinics is the ibogaine hydrochloride salt.
In 1957, prior to ibogaine’s use in the treatment of drug addiction, Ciba Pharmaceutical patented its use for the purpose of enhancing the analgesic effects of opiates.
The mechanism by which Ibogaine potentiates the analgesia of opiates is apparently by an enhancement in opiate signaling and not because of agonistic or antagonistic binding at opiate receptors. In the late 1950’s and 1960’s ibogaine was utilized as an adjunct to psychiatric treatment; possession of ibogaine was made illegal in the U.S. in 1967.
In 1970 the U.S. Food and Drug Administration classified ibogaine as a “Schedule I drug” along with scores of other psychoactive substances, including the better known and more widely used tryptamines LSD and psilocybin. Today ibogaine is unregulated in most nations but is illegal in the U.S., Australia, Belgium, Denmark, France, Sweden and Switzerland.
Starting in 1989, ibogaine treatments for drug dependence took place in non-medical settings in the
Netherlands with support from NDA International and DASH, the Dutch Addict Self-Help organization, as well as ICASH, the International Coalition of Addict Self-Help.
Roughly 40 to 45 patients were treated in the period from 1989 through 1993. Within a few short years, however, these promising avenues were all blocked. In 1993 the death of a female patient in the Netherlands effectively brought an end to the NDA-funded treatments in the Netherlands and severely dampened Dutch enthusiasm for further funding and research on ibogaine treatment. Development of the clinical trial in Rotterdam was halted even though the official Dutch inquiry found no conclusive role for ibogaine in the patient’s death. In the wake of the denial of official approval for the study of ibogaine in Europe and in the United States, ibogaine became increasingly available in alternative settings.
The far-flung, mostly informal network of ibogaine providers grew with increasing rapidity over the following decade or so. An exhaustive ethnographic study of this “ibogaine medical subculture” estimated that 3,414 individuals (plus the “hidden population” accounting for approximately an additional 20 to 30%) had taken ibogaine outside of West Central Africa as of February of 2006, a roughly fourfold increase relative to the cumulative total 5 years earlier. Of the total, 68% had ingested ibogaine for the treatment of a substance-abuse disorder, and 53% specifically for treatment of opioid dependence. A sizeable minority had taken ibogaine for the purpose of promoting personal psycho-spiritual growth.
Typical clinical usage for interrupting addiction involves the ingestion of the hydrochloride salt of ibogaine (ibogaine HCl) at a dosage of 15 to 20 mg/kg of the patient’s body weight, whereas usage for psycho-spiritual purposes typically involves dosages roughly half as strong. The form of ibogaine used most often in the clinical setting is ibogaine HCl of 95 to 98% purity prepared from extracts of the root bark. A 13-step synthesis of ibogaine from nicotinamide has been described but ibogaine can also be produced by semi-synthesis from voacangine, an alkaloid found in Voacanga Africana.
For the treatment of substance dependence, ibogaine has most commonly been administered in a non-hospital setting in the morning, most commonly in the form of a single dose of ibogaine HCl. The patient lies still and awake in a quiet, darkened room for the duration of the treatment; reports of ataxia and sudden vomiting within the first several hours are common. Following the administration of the ibogaine, the subject experiences a sharp reduction in drug cravings and signs of withdrawal within 1-2 hours. Patients commonly report sustained resolution of the withdrawal syndrome within 12-18 hours and a reduction in or absence of drug cravings lasting for at least a few days and sometimes up to two months.
4. Mechanism of action
Initially, ibogaine’s mechanism of actionwas hypothesized to involve antagonism at the N-methyl-d- spartate-type glutamate (NMDA) receptor. However, 18-MC, which has negligible NMDA receptor affinity, also reduces opiate withdrawal and drug self-administration in the animal model. Antagonism of the 34 nicotinic acetylcholine receptor (nAChR) is a possible mechanism of action, as indicated by a series of studies of iboga alkaloids and nicotinic agents. The 34 nAChR is relatively concentrated in the medial habenula and interpeduncular nucleus, where 18-MC’s antagonism of 34 nAChRs diminishes sensitized dopamine efflux in the Nac.
Ibogaine’s mechanism of action has frequently been suggested to involve the modification of neuroadaptations related to prior drug exposure. Ibogaine may modulate intracellular signaling linked to opioid receptors, and potentiates the morphine-induced inhibition of adenylyl cyclase (AC), an effect that is opposite to the activation of AC that is classically associated with opioid withdrawal; Increased glial cell line-derived neurotrophic factor (GDNF) in the ventral tegmental area; has been suggested to mediate decreased ethanol consumption following the administration of ibogaine to rats. GDNF enhances the regeneration of dopaminergic function and is increased by antidepressant treatment . The hypothesis that GDNF may mediate improvement in hedonic functioning and mood in chronic withdrawal from addictive substances is appealing, but does not appear likely to explain efficacy in acute opioid withdrawal. Although designated as a hallucinogen, ibogaine’s use in opioid withdrawal distinguishes it from other compounds that are commonly termed “psychedelics”, namely the serotonin type 2A receptor agonist classical hallucinogens such as lysergic acid diethylamide (LSD), psilocybin and mescaline, or the serotonin releasing substituted amphetamine 3,4-methylenedioxymethamphetamine (MDMA). In contrast with ibogaine, there is no preclinical or case report evidence that suggests a significant therapeutic effect of classical hallucinogens or MDMA in acute opioid withdrawal. Ibogaine’s effects in opioid withdrawal do not appear to involve serotonin agonist or releasing activity. Serotonergic neurotransmission does not appear to play a significant role in mediating the expression of the opioid withdrawal syndrome, which remains unchanged even after extensive lesioning of the raphe.
5. Cardiac Interaction with hERG channels
The drug has propensity to inhibit human ERG (hERG, IKr) potassium currents. hERG channels are crucial for the repolarisation phase of the cardiac action potential (AP), and hERG channel blockade by drugs is considered the most common reason for drug-induced QT interval prolongation, which can be associated with an increased cardiac arrhythmia risk. It has been recently reported that ibogaine concentrations in the low micromolar range inhibit hERG channels expressed in TSA-201 cells. Here, has been characterised ibogaine's effects on hERG channels in more detail. In addition, has been also tested the effects of its congener 18-Methoxycoronaridine.
Ibogaine concentrations have been measured in whole blood samples of humans after single oral doses of 500–1000 mg, doses that are typically employed to treat drug addicts (10–25 mg/kg of body weight), and in a case of ibogaine poisoning. The values obtained were 1–10 μg/ml (3–30 μM) and represent total drug concentrations. With the extent of ibogaine's human plasma protein binding of 65% taken into account, the free plasma concentrations reached after drug intake in these studies amounted to 1–11 μM. Together, this suggests that therapeutic concentrations of ibogaine directly inhibit hERG channels in the human heart. Ibogaine is known to affect the cardiovascular system. The drug slows the heart rate in animals and humans. This effect is probably mediated via interaction of ibogaine with muscarinic acetylcholine receptors. Moreover, cardiac arrhythmias have been related to several cases of sudden death after ibogaine intake.
However, due to concomitant medications used and comorbidities (e.g. cardiovascular) present in the patients described in these cases, it is unclearwhether indeed ibogaine has caused these deaths. Has been described both ibogaine effects on cardiac ion channels that favour (hERG channel inhibition) and counteract (calcium channel inhibition) AP prolongation. Because ibogaine's affinity for human ERG channels is considerably higher (40-fold) than that for human Cav1.2 channels, has been proposed that the drug can prolong AP duration in human ventricular cardiomyocytes, and thereby has the propensity to prolong the QT interval. It should be noted here, however, that although most probably insufficient to fully counteract AP prolongation due to hERG channel inhibition, calcium channel blockade will in any case diminish the amount of QT interval prolongation generated by the drug another consideration is noteworthy: reported cases of QT interval prolongation after ibogaine intake in humans were all accompanied by hypokalaemia. Hypokalaemia has been shown to reduce the cell surface density of hERG channels, and exacerbates long QT syndrome. Thus, it cannot unequivocally be judged, whether the cases of QT prolongation reported can solely be attributed to the direct inhibitory effect of ibogaine on hERG channels in these patients. Moreover, low extracellular potassium may also increase drug blockade of IKr. If this is also true for ibogaine, hypokalaemia may enhance the direct QT prolonging effect of the drug via hERG channel inhibition. Finally, besides QT prolongation as a possible consequence of hERG inhibition, it should be noted that the application of a powerful psychoactive drug such as ibogaine may also lead to cardiac adverse effects related to its central nervous activity without the need to imply hERG inhibition.
Regardless of the actual mechanism underlying the potential ibogaine-induced QT prolongation, this condition may likely be detrimental for humans at high risk such as in the case of drug addicts. Besides ibogaine, its synthetic congener 18-MC, is believed to be less toxic. It has been found that, similar to ibogaine, 18-MC inhibits hERG and hNav1.5 channels heterologously expressed in TSA-201 cells. For the inhibition of both these currents, however, higher concentrations of 18-MC were needed when compared to ibogaine. This suggests that the affinity of 18-MC to cardiac voltage-gated ion channels is lower than that of ibogaine. It has been reported that 18-MC has a lower affinity for rat brain sodium channels than ibogaine. In principle, the lower affinities of 18-MC for cardiac ion channels suggest a reduced risk for cardiac adverse effects in comparison with ibogaine. However, 18-MC's affinity for hERG channels (IC50, 15 μM) is still close to the therapeutic concentration range (see above), if similar plasma protein binding as for ibogaine is assumed.
Thus, like ibogaine, 18-MC may have the propensity to induce QT interval prolongation by hERG channel inhibition. 3- to 4-fold higher concentrations of 18-MC, however, may be needed to trigger this effect. Finally, it should be mentioned that a racemate of 18-MC was used here for testing. This may restrict the conclusions drawn, because single enantiomers could possess different ion channel activities.
The current inhibition data used for the human AP computer simulations originated from human ion channels (hERG, hNav1.5, and hCav1.2) heterologously expressed in TSA-201 cells. Drug affinities for ion channels in native cells can differ from those detected in heterologous expression systems. Thus, the simulations can only provide an estimate of the real situation in native human cardiomyocytes. This certainly limits the predictions about ibogaine's effects on the heart's electrophysiology in humans. It has been also aware that, by assessing the cardiac ion channel profile of ibogaine (and 18-MC), has been not directly test proarrhythmia liability or vulnerability.
In conclusion, it has been found that ibogaine inhibits cardiac voltagegated ion channels. At therapeutic concentrations, the drug's inhibitory effect on hERG channels provides a potential explanation for the reported QT interval prolongation in humans that may lead in some cases to tachyarrhythmias. Ibogaine derivatives with reduced propensity to block cardiac ion channels but preserved anti-addictive properties need to be developed. 18-MC may be regarded as a first candidate.