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J. Howes

Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents

April 4, 2016 / Iboga / Ibogaine, Neuroscience, Papers, Publications, Substance Use Disorder / By / , , , ,

Abstract

This study investigated the effects of noribogaine, the principal metabolite of the drug ibogaine, on substance-related disorders. In the first experiment, mice chronically treated with morphine were subjected to naloxone-precipitated withdrawal two hours after oral administration of noribogaine. Oral noribogaine dose dependently decreased the global opiate withdrawal score by up to 88% of vehicle control with an ED50of 13 mg/kg. In the second experiment, blood and brain levels of noribogaine showed a high brain penetration and a brain/blood ratio of 7±1 across all doses tested. In a third experiment, rats given oral noribogaine up to 100 mg/kg were tested for abuse liability using a standard biased conditioned place paradigm. Noribogaine-treated rats did not display place preference, suggesting that noribogaine is not perceived as a hedonic stimulus in rodents. Retrospective review of published studies assessing the efficacy of ibogaine on morphine withdrawal shows that the most likely cause of the discrepancies in the literature is the different routes of administration and time of testing following ibogaine administration. These results suggest that the metabolite noribogaine rather than the parent compound mediates the effects of ibogaine on blocking naloxone-precipitated withdrawal. Noribogaine may hold promise as a non-addicting alternative to standard opiate replacement therapies to transition patients to opiate abstinence.

Mash, D. C., Ameer, B., Prou, D., Howes, J. F., & Maillet, E. L. (2016). Oral noribogaine shows high brain uptake and anti-withdrawal effects not associated with place preference in rodents. Journal of psychopharmacology (Oxford, England). http://dx.doi.org/10.1177/0269881116641331

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Ascending single-dose, double-blind, placebo-controlled safety study of noribogaine in opioid-dependent patients

February 10, 2016 / Iboga / Ibogaine, Papers, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine’s active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled, single ascending dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST, who had been switched to morphine during the previous week. Noribogaine doses were 60, 120 or 180mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were non-euphoric changes in light perception at ∼1h post dose, headache and nausea. Noribogaine had dose-linear increases for AUC and Cmax, and was slowly eliminated (mean t1/2 range 24–30h). There was a concentration-dependent increase in QTcI (0.17msec/ng/mL) with largest observed mean effect of ∼16msec, 28msec, and 42msec in the 60mg, 120mg, and 180mg groups, respectively. Noribogaine showed a non-statistically significant trend to decrease total scores in opioid withdrawal ratings, most notably at the 120mg dose, however the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues.

Glue, P., Cape, G., Tunnicliff, D., Lockhart, M., Lam, F., Hung, N., … & Howes, J. (2016). Ascending single‐dose, double‐blind, placebo‐controlled safety study of noribogaine in opioid‐dependent patients. Clinical Pharmacology in Drug Development. http://dx.doi.org/10.1002/cpdd.254
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