Ibogaine for treating drug dependence. What is a safe dose?

The paper reviews pharmacology and toxicology data from in vitro, animal and human reports. Ibogaine has complex pharmacology, interacting with multiple targets including sigma-2, kappa- and mu-opioid, 5-HT2 and 5-HT3 receptors, α3β4 nicotinic receptors, the NMDA channel, and the serotonin transporter. The authors report radioligand and functional data indicating micromolar affinity at many sites (IC50s roughly 1–10 µM), and note that oral administration in rats (50 mg/kg) produced brain concentrations of about 4–17 µM, i.e. within the range of in vitro affinities. Animal acute toxicity varies by species and route. Reported lethal doses (LD50 ranges) in rodents were approximately 145–175 mg/kg by intraperitoneal (IP) injection and 263–327 mg/kg by the oral route. A NOAEL (no observable adverse effect level) of 25 mg/kg IP was reported in one rat study, where neuronal injury (Purkinje cell pathology) appeared at 50 mg/kg IP and higher. Tremor is a common sign in rodents, reported at doses as low as 12 mg/kg subcutaneous and at higher IP doses (40–100 mg/kg). Cardiac effects in animals included bradycardia and, variably, hypotension at doses from 50 mg/kg IP upward, though ECG monitoring was not consistently reported. To estimate human risk, the authors apply standard inter- and intra-species safety factors to animal NOAELs. They point out that the NOAEL was determined by the IP route only, limiting direct translation to oral dosing. Using a conservative safety factor approach (examples given: dividing the lowest reported lethal oral dose of 263 mg/kg by factors for intra-species variability, inter-species conversion and susceptible subpopulations), the authors calculate theoretical starting human oral doses on the order of about 0.8–0.9 mg/kg. They note that a 1995 FDA-approved clinical trial initiated doses at 1–2 mg/kg and that a more recent controlled study used a 20 mg single dose (approximately 0.25 mg/kg for an 80 kg person) without major toxicity. In contrast, doses reported in unregulated clinic settings have ranged from 6 to 30 mg/kg, which overlap with ranges associated with animal toxicity. Human adverse effects reported in case series and case reports include nausea, vomiting, tremor, ataxia, seizures, respiratory compromise and pulmonary aspiration. The principal cardiac concern is drug-induced QT interval prolongation with risk of torsades de pointes and ventricular fibrillation. In vitro patch-clamp studies report hERG (human Ether-à-go-go Related Gene) channel inhibition by ibogaine with IC50 values of about 3.53–4.1 µM; the authors highlight that these concentrations are similar to anticipated clinical plasma or brain concentrations following higher therapeutic doses. Case reports and emergency department data cite blood concentrations of about 377 ng/mL and ~950 ng/mL associated with QT prolongation. The paper also discusses metabolic variability: CYP2D6 poor metabolisers may achieve higher ibogaine exposure and thus greater toxicity risk. Finally, the authors summarise a review of 19 deaths reported after ibogaine treatment between 1990 and 2008: 15 deaths occurred during detoxification, two were associated with spiritual/psychoactive experiences, and two were of unknown cause.

Schep and colleagues conclude that, despite popularity as an alternative treatment for drug dependence, ibogaine’s toxicity data are limited and doses associated with behavioural effects in animals overlap with doses that cause neuronal injury and block cardiac hERG potassium channels. Human reports have documented serious adverse events including seizures, cardiac dysrhythmias and death. Given the sparse data, the authors recommend a conservative maximal oral dose of less than 1 mg/kg for humans based on animal NOAELs and application of standard safety factors, with any subsequent dose escalation only within rigorously monitored clinical trials that track indices of human toxicity. They further state that, until a safe and efficacious human dose is established, a moratorium on clinical use outside controlled research settings should be considered to prevent further avoidable deaths, particularly among patients with comorbidities common in long-term drug users.