Multiple lines of evidence point to mitochondrial oxidative stress as a potential pathogenic cause for Parkinson's disease (PD). MitoQ is a powerful mitochondrial antioxidant. It is absorbed orally and concentrates within mitochondria where it has been shown to protect against oxidative damage. We enrolled 128 newly diagnosed untreated patients with PD in a double-blind study of two doses of MitoQ compared with placebo to explore the hypothesis that, over 12 months, MitoQ would slow the progression of PD as measured by clinical scores, particularly the Unified Parkinson Disease Rating Scale. We showed no difference between MitoQ and placebo on any measure of PD progression. MitoQ does not slow the progression of PD, and this finding should be taken into account when considering the oxidative stress hypothesis for the pathogenesis of PD.

Administration of the mitochondria-targeted anti-oxidant mitoquinone significantly decreased plasma ALT and aspartate aminotransferase in patients with chronic HCV infection, and this suggests that mitoquinone may decrease necroinflammation in the liver in these patients. As mitochondrial oxidative damage contributes to many other chronic liver diseases, such as steatohepatitis, further studies using mitochondria-targeted anti-oxidants in HCV and other liver diseases are warranted.

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers.

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 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and C and was slowly eliminated (mean t range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg 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.

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ObjectiveBecause clozapine and risperidone have been shown to reduce neuroinflammation in humans and mice, the Clozapine and Risperidone in Progressive Multiple Sclerosis (CRISP) trial was conducted to determine whether clozapine and risperidone are suitable for progressive multiple sclerosis (pMS).MethodsThe CRISP trial (ACTRN12616000178448) was a blinded, randomised, placebo-controlled trial with three parallel arms (n=12/arm). Participants with pMS were randomised to clozapine (100–150 mg/day), risperidone (2.0–3.5 mg/day) or placebo for 6 months. The primary outcome measures were safety (adverse events (AEs)/serious adverse events (SAE)) and acceptability (Treatment Satisfaction Questionnaire for Medication-9).ResultsAn interim analysis (n=9) revealed significant differences in the time-on-trial between treatment groups and placebo (p=0.030 and 0.025, clozapine and risperidone, respectively) with all participants receiving clozapine being withdrawn during the titration period (mean dose=35±15 mg/day). Participants receiving clozapine or risperidone reported a significantly higher rate of AEs than placebo (p=0.00001) but not SAEs. Specifically, low doses of clozapine appeared to cause an acute and dose-related intoxicant effect in patients with pMS who had fairly severe chronic spastic ataxic gait and worsening over all mobility, which resolved on drug cessation.InterpretationThe CRISP trial results suggest that patients with pMS may experience increased sensitivity to clozapine and risperidone and indicate that the dose and/or titration schedule developed for schizophrenia may not be suitable for pMS. While these findings do not negate the potential of these drugs to reduce multiple sclerosis-associated neuroinflammation, they highlight the need for further research to understand the pharmacodynamic profile and effect of clozapine and risperidone in patients with pMS.Trial registration numberACTRN12616000178448.